JP5490778B2 - Fluorinated macrocycles as hepatitis C virus inhibitors - Google Patents

Description

(Related application)
This application claims the benefit of US Provisional Application No. 61 / 038,096, filed Mar. 20, 2008. The entire teachings of the above application are incorporated herein by reference.

(Technical field)
The present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds that have antiviral activity against HCV and are useful in the treatment of HCV infection. More particularly, the invention relates to fluorinated macrocycle compounds, compositions containing such compounds, and methods for using them, and methods for making such compounds.

(Background of the Invention)
HCV is a major cause of non-A and non-B hepatitis and is becoming a serious public health problem in both developed and developing countries. It is estimated that more than 200 million people worldwide are infected with the virus, almost five times as many as human immunodeficiency virus (HIV). Patients infected with HCV have a high probability of suffering from chronic infections, and therefore have a high risk of developing cirrhosis, advanced hepatocellular carcinoma and end-stage liver disease. HCV is the most common cause of hepatocellular carcinoma and the most common cause for patients in Western countries to desire a liver transplant.

  There are many obstacles to the development of anti-HCV therapies including, but not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, and the resistance of the virus to express drug-resistant mutants. The high incidence and lack of reproducible infection culture systems and small animal models for HCV replication and lesion formation. In most cases, given the mild course of infection and the complex biology of the liver, antiviral drugs that have the potential for serious side effects must be carefully considered.

  Currently, only two approved HCV infection treatments are available. Initial treatment regimens generally include a 3 to 12 month intravenous interferon α (IFN-α) dosing process, but subsequently approved second generation therapies are common anti-tumor agents such as IFN-α and ribavirin. Includes combination therapy with viral nucleoside mimetics. Both of these therapies suffer from interferon-related side effects, as well as low efficacy against HCV infection. Due to the low tolerability and disappointing effectiveness of existing therapies, it is necessary to develop antiviral agents effective in treating HCV infection.

  In patient populations where the majority of individuals are chronically infected, asymptomatic, and the prognosis is unknown, it is desirable that effective drugs have significantly fewer side effects than currently available treatments. Hepatitis C nonstructural protein 3 (NS3) is a proteolytic enzyme required for viral polyprotein processing and consequently viral replication. Despite the enormous number of viral variants associated with HCV infection, the active site of NS3 protease remains highly conserved, thus inhibiting it is an attractive therapeutic intervention. Recent success in HIV treatment with protease inhibitors supports the notion that inhibition of NS3 is an important target in the fight against HCV.

  HCV is a Flaviviridae RNA virus. The HCV genome is enveloped and contains single-stranded RNA molecules composed of approximately 9600 base pairs. This encodes a polypeptide composed of about 3010 amino acids.

  HCV polyproteins are processed by viruses and host peptidases into 10 separate peptides that perform various functions. There are three structural proteins, C, E1 and E2. The P7 protein has an unknown function and is composed of a highly variable sequence. There are 6 nonstructural proteins. NS2 is a zinc-dependent metalloproteinase that functions with a portion of the NS3 protein. NS3 combines the functions of two catalytic functions (except for association with NS2): a serine protease at the N-terminus that requires NS4A as a cofactor and an ATPase-dependent helicase at the carboxyl terminus. NS4A is a closely related but not covalently linked cofactor of serine proteases.

  NS3-NS4A protease is involved in cleaving four sites on the viral polyprotein. NS3-NS4A cleavage is autocatalytic and occurs in cis. The remaining three hydrolyzed NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans. NS3 is a serine protease that is structurally classified as a chymotrypsin-like protease. While NS serine protease itself has proteolytic activity, the HCV protease enzyme is not an effective enzyme in catalyzing the cleavage of polyproteins. The central hydrophobic region of the NS4A protein has been shown to be necessary for this enhancement. Complex formation of NS3 protein with NS4A appears to be necessary for processing events and enhances protein resolution at all of the sites.

  A common strategy for antiviral development is to inactivate virally encoded enzymes, including NS3, that are essential for viral replication. Current results for the discovery of NS3 protease inhibitors include Tan, A.M. Pause, Y.M. Shi, N .; Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002).

S. Tan, A.M. Pause, Y.M. Shi, N .; Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002)

(Summary of the Invention)
The present invention relates to fluorinated macrocyclic compounds, and pharmaceutically acceptable salts, esters or prodrugs thereof, and methods for using them to treat hepatitis C infection in a subject in need of such treatment. About. The compounds of the present invention interfere with the life cycle of hepatitis C virus and are also useful as antiviral agents. The present invention further relates to a pharmaceutical composition comprising a compound, salt, ester or prodrug as described above for administration to a subject suffering from HCV infection. The present invention further includes a compound of the invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and an interferon (eg, α-interferon, β-interferon, consensus interferon, pegylated interferon or albumin or other binding) Interferon), another anti-HCV agent such as ribavirin, amantadine, another HCV protease inhibitor, or a pharmaceutical composition comprising an HCV polymerase, helicase or intra-sequence ribosome entry site inhibitor. The invention also relates to a method of treating HCV infection in a subject by administering to the subject a pharmaceutical composition of the invention. The invention further relates to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.

  In one embodiment of the invention, compounds of formula I, or pharmaceutically acceptable salts, esters or prodrugs thereof are disclosed.

［式中、
Ｒは、
（ｉ）それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_８アルキル、−Ｃ_２−Ｃ_８アルケニルまたは−Ｃ_２−Ｃ_８アルキニル；それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_８アルキル、置換−Ｃ_２−Ｃ_８アルケニルまたは置換−Ｃ_２−Ｃ_８アルキニル；−Ｃ_３−Ｃ_１２シクロアルキルまたは置換−Ｃ_３−Ｃ_１２シクロアルキル；−Ｃ_４−Ｃ_１２アルキルシクロアルキルまたは置換−Ｃ_４−Ｃ_１２アルキルシクロアルキル；−Ｃ_３−Ｃ_１２シクロアルケニルまたは置換−Ｃ_３−Ｃ_１２シクロアルケニル；−Ｃ_４−Ｃ_１２アルキルシクロアルケニルまたは置換−Ｃ_４−Ｃ_１２アルキルシクロアルケニル、
（ｉｉ）アリール；置換アリール；ヘテロアリール；置換ヘテロアリール、
（ｉｉｉ）ヘテロシクロアルキルまたは置換ヘテロシクロアルキル、
（ｉｖ）水素；重水素
からなる群から選択され、
Ａは存在しない、または−（Ｃ＝Ｏ）−、−Ｓ（Ｏ）_２、−Ｃ＝Ｎ−ＯＲ_１もしくは−Ｃ（＝Ｎ−ＣＮ）から選択され、Ｒ_１は、
（ｉ）水素、
（ｉｉ）アリール；置換アリール；ヘテロアリール；置換ヘテロアリール、
（ｉｉｉ）ヘテロシクロアルキルまたは置換ヘテロシクロアルキル、
（ｉｖ）それぞれがＯ、Ｓ、またはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_８アルキル、−Ｃ_２−Ｃ_８アルケニルまたは−Ｃ_２−Ｃ_８アルキニル；それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_８アルキル、置換−Ｃ_２−Ｃ_８アルケニルまたは置換−Ｃ_２−Ｃ_８アルキニル；−Ｃ_３−Ｃ_１２シクロアルキルまたは置換−Ｃ_３−Ｃ_１２シクロアルキル；−Ｃ_３−Ｃ_１２シクロアルケニルまたは置換−Ｃ_３−Ｃ_１２シクロアルケニル
からなる群から選択され、
Ｌ_２０１は存在しない、またはそれぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_１−Ｃ_１２アルキレン、−Ｃ_２−Ｃ_１２アルケニレンもしくは−Ｃ_２−Ｃ_１２アルキニレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_１２アルキレン、置換−Ｃ_２−Ｃ_１２アルケニレンもしくは置換−Ｃ_２−Ｃ_１２アルキニレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_３−Ｃ_１２シクロアルキレンもしくは置換−Ｃ_３−Ｃ_１２シクロアルキレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_３−Ｃ_１２シクロアルケニレンもしくは置換−Ｃ_３−Ｃ_１２シクロアルケニレンから選択され、
Ｍは存在しない、またはＯ、Ｓ、ＳＯ、ＳＯ_２もしくはＮＲ_１（Ｒ_１はすでに定義されている通りである。）から選択され、
Ｌ_１０１は存在しない、またはそれぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_１−Ｃ_１２アルキレン、−Ｃ_２−Ｃ_１２アルケニレンもしくは−Ｃ_２−Ｃ_１２アルキニレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_１２アルキレン、置換−Ｃ_２−Ｃ_１２アルケニレンもしくは置換−Ｃ_２−Ｃ_１２アルキニレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_３−Ｃ_１２シクロアルキレンもしくは置換−Ｃ_３−Ｃ_１２シクロアルキレン；それぞれがＯ、ＳもしくはＮから選択される０、１、２もしくは３個のヘテロ原子を含有する−Ｃ_３−Ｃ_１２シクロアルケニレンもしくは置換−Ｃ_３−Ｃ_１２シクロアルケニレンから選択され、
Ｚ_１０１は存在しない、またはＭ、アリール、置換アリール、ヘテロアリールもしくは置換ヘテロアリールから選択され、
Ｇは、−ＯＨ、−ＮＨ（ＳＯ_２）Ｒ_２、−ＮＨ（ＳＯ_２）ＮＲ_３Ｒ_４およびＮＲ_３Ｒ_４から選択され、
Ｒ_２は、
（ｉ）アリール；置換アリール；ヘテロアリール；置換ヘテロアリール、
（ｉｉ）ヘテロシクロアルキル；置換ヘテロシクロアルキル、
（ｉｉｉ）それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_８アルキル、−Ｃ_２−Ｃ_８アルケニルまたは−Ｃ_２−Ｃ_８アルキニル、それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_８アルキル、置換−Ｃ_２−Ｃ_８アルケニルまたは置換−Ｃ_２−Ｃ_８アルキニル；−Ｃ_３−Ｃ_１２シクロアルキルまたは置換−Ｃ_３−Ｃ_１２シクロアルキル；−Ｃ_３−Ｃ_１２シクロアルケニルまたは置換−Ｃ_３−Ｃ_１２シクロアルケニル；複素環；置換複素環
から選択され、
Ｒ_３およびＲ_４は、
（ｉ）水素、
（ｉｉ）アリール；置換アリール；ヘテロアリール；置換ヘテロアリール、
（ｉｉｉ）ヘテロシクロアルキルまたは置換ヘテロシクロアルキル、
（ｉｖ）それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_８アルキル、−Ｃ_２−Ｃ_８アルケニルまたは−Ｃ_２−Ｃ_８アルキニル；それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_８アルキル、置換−Ｃ_２−Ｃ_８アルケニルまたは置換−Ｃ_２−Ｃ_８アルキニル；−Ｃ_３−Ｃ_１２シクロアルキルまたは置換−Ｃ_３−Ｃ_１２シクロアルキル；−Ｃ_３−Ｃ_１２シクロアルケニルまたは置換−Ｃ_３−Ｃ_１２シクロアルケニル；複素環または置換複素環
から独立して選択され、
あるいは、Ｒ_３およびＲ_４は、これらが結合している窒素と一緒になって、複素環または置換複素環を形成し、
Ｑ_１およびＱ_２は、ハロゲン；好ましくはＦ、ＣｌおよびＢｒから独立して選択され、
Ｘは存在しない、または
（１）酸素、
（２）硫黄、
（３）ＮＲ_４；（Ｒ_４はすでに上記で定義されている通りである。）、
（４）−Ｏ−ＮＨ−
からなる群から選択され、
Ｙは存在しない、または
（ｉ）−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＨ−、−Ｓ（Ｏ）２−、−Ｓ（Ｏ）２ＮＨ−、
（ｉｉ）ハロゲン、アリール、置換アリール、ヘテロアリールまたは置換ヘテロアリールから選択される１個以上の置換基で任意に置換されている、Ｏ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_６アルキル、
（ｉｉｉ）ハロゲン、アリール、置換アリール、ヘテロアリールまたは置換ヘテロアリールから選択される１個以上の置換基で任意に置換されている、Ｏ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_２−Ｃ_６アルケニル、
（ｉｖ）ハロゲン、アリール、置換アリール、ヘテロアリールまたは置換ヘテロアリールから選択される１個以上の置換基で任意に置換されている、Ｏ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_２−Ｃ_６アルキニル、
（ｖ）−Ｃ_３−Ｃ_１２シクロアルキル、置換−Ｃ_３−Ｃ_１２シクロアルキル、ヘテロシクロアルキル、置換ヘテロシクロアルキル
からなる群から選択され、
Ｗは、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、シクロアルキル、置換シクロアルキル、ヘテロシクロアルキル、置換ヘテロシクロアルキルからなる群から選択され、これらのそれぞれは１つ以上のアリール、置換アリール、ヘテロアリール；置換ヘテロアリール、シクロアルキル、置換シクロアルキル、ヘテロシクロアルキルと任意に縮合しており、
または−Ｘ−Ｙ−Ｗは一緒になって

[Where:
R is
(I) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- , each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N C _{8 alkynyl;} -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 4 _{-C 12} alkylcycloalkyl, or substituted _-C 4 _{-C 12 alkylcycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12 cycloalkenyl;} -C 4 _{-C 12} alkyl cycloalkenyl or substituted _-C 4 _{-C 12} alkyl cycloalkenyl,
(Ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Iii) heterocycloalkyl or substituted heterocycloalkyl,
(Iv) hydrogen; selected from the group consisting of deuterium;
A is absent or selected from — (C═O) —, —S (O) ₂ , —C═N—OR ₁ or —C (═N—CN), wherein R ₁ is
(I) hydrogen,
(Ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Iii) heterocycloalkyl or substituted heterocycloalkyl,
(Iv) each O, S or _-C 1 -C ₈ alkyl containing 0, 1, 2 or 3 heteroatoms selected from N,, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C ₂ each containing 0, 1, 2 or 3 heteroatoms, each selected from O, S or N It is selected from -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} group consisting of _{cycloalkenyl,;} -C _{8 alkynyl;} -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12} cycloalkyl
L ₂₀₁ is absent or —C ₁ -C ₁₂ alkylene, —C ₂ -C ₁₂ alkenylene or —C, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N _2- C ₁₂ alkynylene; substituted -C ₁ -C ₁₂ alkylene, substituted -C ₂ -C ₁₂ alkenylene or substituted, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N -C ₂ -C ₁₂ alkynylene; each O, _-C 3 _{-C 12} cycloalkylene or substituted _-C 3 _{-C 12} cycloalkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N An alkylene; —C ₃ -C ₁₂ cycloa each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N Selected from lukenylene or substituted -C ₃ -C ₁₂ cycloalkenylene,
M is absent or selected from O, S, SO, SO ₂ or NR ₁ (R ₁ is as previously defined);
L ₁₀₁ is absent or —C ₁ -C ₁₂ alkylene, —C ₂ -C ₁₂ alkenylene or —C, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N _2- C ₁₂ alkynylene; substituted -C ₁ -C ₁₂ alkylene, substituted -C ₂ -C ₁₂ alkenylene or substituted, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N -C ₂ -C ₁₂ alkynylene; each O, _-C 3 _{-C 12} cycloalkylene or substituted _-C 3 _{-C 12} cycloalkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N An alkylene; —C ₃ -C ₁₂ cycloa each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N Selected from lukenylene or substituted -C ₃ -C ₁₂ cycloalkenylene,
Z ₁₀₁ is absent or selected from M, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
G is selected from —OH, —NH (SO ₂ ) R ₂ , —NH (SO ₂ ) NR ₃ R ₄ and NR ₃ R ₄ ;
R ₂ is
(I) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Ii) heterocycloalkyl; substituted heterocycloalkyl;
(Iii) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl, substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- containing 0, 1, 2 or 3 heteroatoms, each selected from O, S or N C _{8 alkynyl;} selected from substituted heterocycle; -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} cycloalkenyl; heterocyclic And
R ₃ and R ₄ are
(I) hydrogen,
(Ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Iii) heterocycloalkyl or substituted heterocycloalkyl,
(Iv) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- , each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N C _{8 alkynyl;} independently heterocyclic or substituted heterocyclic; -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} cycloalkenyl Selected,
Alternatively, R ₃ and R ₄ together with the nitrogen to which they are attached form a heterocycle or substituted heterocycle,
Q ₁ and Q ₂ are independently selected from halogen; preferably F, Cl and Br;
X is absent, or (1) oxygen,
(2) sulfur,
(3) NR ₄ ; (R ₄ is as defined above),
(4) -O-NH-
Selected from the group consisting of
Y is absent, or (i) -C (= O)-, -C (= O) -NH-, -S (O) 2-, -S (O) 2NH-,
(Ii) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 1 -C ₆ alkyl containing pieces of heteroatoms,
(Iii) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 2 -C ₆ alkenyl containing number of hetero atoms,
(Iv) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 2 -C ₆ alkynyl containing pieces of heteroatoms,
_{(V) -C} 3 -C ₁₂ cycloalkyl, substituted _-C 3 _{-C 12} cycloalkyl, heterocycloalkyl, selected from the group consisting of substituted heterocycloalkyl,
W is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, each of which is one or more aryl, substituted aryl, Heteroaryl; optionally fused with substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
Or -X-Y-W together

を形成し、式中、各Ｗ_１、Ｗ_２は、
ｉ）水素、
ｉｉ）アリール、
ｉｉｉ）置換アリール、
ｉｖ）ヘテロアリール、
ｖ）置換ヘテロアリール、
ｖｉ）複素環または置換複素環、
ｖｉｉ）それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する−Ｃ_１−Ｃ_８アルキル、−Ｃ_２−Ｃ_８アルケニルまたは−Ｃ_２−Ｃ_８アルキニル、
ｖｉｉｉ）それぞれがＯ、ＳまたはＮから選択される０、１、２または３個のヘテロ原子を含有する置換−Ｃ_１−Ｃ_８アルキル、置換−Ｃ_２−Ｃ_８アルケニルまたは置換−Ｃ_２−Ｃ_８アルキニル、
ｉｘ）−Ｃ_３−Ｃ_１２シクロアルキル、
ｘ）置換−Ｃ_３−Ｃ_１２シクロアルキル、
ｘｉ）−Ｃ_３−Ｃ_１２シクロアルケニル、
ｘｉｉ）置換−Ｃ_３−Ｃ_１２シクロアルケニル
からなる群から独立して選択され、
またはＷ_１およびＷ_２はこれらが結合している炭素原子と一緒になって、−Ｃ_３−Ｃ_８シクロアルキル、−Ｃ_３−Ｃ_８シクロアルケニル、複素環、置換−Ｃ_３−Ｃ_８シクロアルキル、置換−Ｃ_３−Ｃ_８シクロアルケニルおよび置換複素環からなる群から選択される環状部分を形成し、これらのそれぞれは１つ以上のアリール、置換アリール、ヘテロアリール；置換ヘテロアリール、複素環または置換複素環と任意に縮合しており、
ただし、Ｘが酸素であり、Ｙが存在しない場合、Ｗはキノキサリンを含有していない（Ｘ−Ｙ−Ｗは

Where each W ₁ , W ₂ is
i) hydrogen,
ii) aryl,
iii) substituted aryl,
iv) heteroaryl,
v) substituted heteroaryl,
vi) a heterocycle or substituted heterocycle,
vii) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ alkynyl ,
viii) each is O, substituted _-C 1 -C ₈ alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, substituted _-C 2 -C ₈ alkenyl, or substituted -C ₂ - C ₈ alkynyl,
_{ix) -C} 3 -C ₁₂ cycloalkyl,
x) substituted _-C 3 _{-C 12} cycloalkyl,
_{xi) -C} 3 -C ₁₂ cycloalkenyl,
xii) independently selected from the group consisting of substituted _-C 3 _{-C 12} cycloalkenyl,
Or W ₁ and W ₂ together with the carbon atom to which they are attached, —C ₃ -C ₈ cycloalkyl, —C ₃ -C ₈ cycloalkenyl, heterocycle, substituted —C ₃ -C ₈ cyclo Forming a cyclic moiety selected from the group consisting of alkyl, substituted —C ₃ -C ₈ cycloalkenyl and substituted heterocycle, each of which is one or more aryl, substituted aryl, heteroaryl; substituted heteroaryl, heterocycle Or optionally condensed with a substituted heterocycle,
However, when X is oxygen and Y is not present, W does not contain quinoxaline (X—Y—W is

を含有していない。）こと、またはキノキサリンから誘導される任意の部分を含有していない（Ｘ−Ｙ−Ｗは

Does not contain. Does not contain any moiety derived from quinoxaline (X—Y—W is

を含有していない。）ことを条件とし、
ｍは、０、１、２または３であり、
ｍ’は、０、１、２または３であり、
ｓは、１、２、３または４である。］

Does not contain. )
m is 0, 1, 2 or 3;
m ′ is 0, 1, 2 or 3,
s is 1, 2, 3 or 4. ]

  In another embodiment, the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof. In yet another embodiment of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient. It is disclosed. Yet another embodiment of the invention is a method of treating hepatitis C infection in a subject in need of such treatment using the pharmaceutical composition.

(Detailed description of the invention)
A first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient. is there.

  Another embodiment of the present invention is a compound of formula II, alone or in combination with a pharmaceutically acceptable carrier or excipient.

によって表される化合物、または医薬として許容できるこの塩、エステルもしくはプロドラッグであり、式中、Ｒ、Ａ、Ｌ_２０１、Ｍ、Ｌ_１０１、Ｚ_１０１、Ｗ、Ｙ、Ｘ、Ｑ_１、Ｑ_２およびＧは、第一の実施形態において定義されている通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , W, Y, X, Q ₁ , Q ₂ And G are as defined in the first embodiment.

    Another embodiment of the present invention is a compound of formula III, alone or in combination with a pharmaceutically acceptable carrier or excipient.

で表される化合物または医薬として許容できるこの塩、エステルもしくはプロドラッグであり、式中、Ｒ、Ａ、Ｌ_２０１、Ｍ、Ｌ_１０１、Ｚ_１０１、Ｗ_１、Ｗ_２、Ｑ_１、Ｑ_２およびＧは、第一実施形態において定義されている通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , W ₁ , W ₂ , Q ₁ , Q ₂ and G is as defined in the first embodiment.

In one example, W ₁ and W ₂ are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or W ₁ and W ₂ are the carbon atoms to which they are attached. together with, _-C 3 -C ₈ cycloalkyl, _-C 3 -C ₈ cycloalkenyl, heterocyclic, substituted _-C 3 -C ₈ cycloalkyl, substituted _-C 3 -C ₈ cycloalkenyl, and substituted heterocyclic Each of which is optionally fused to one or more aryl, substituted aryl, heteroaryl and substituted heteroaryl.

  Other embodiments of the present invention are compounds of formula IV, V and VI, alone or in combination with a pharmaceutically acceptable carrier or excipient.

で表される化合物または医薬として許容できるこれらの塩、エステルもしくはプロドラッグであり、式中、Ｒ_３０１は、Ｈ、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_１２シクロアルキル、−ＣＨ_２−アルキルアミノ、−ＣＨ_２−ジアルキルアミノ、−ＣＨ_２−アリールアミノ、−ＣＨ_２−ジアリールアミノ、−（Ｃ＝Ｏ）−アルキルアミノ、−（Ｃ＝Ｏ）−ジアルキルアミノ、−（Ｃ＝Ｏ）−アリールアミノ、−（Ｃ＝Ｏ）−ジアリールアミノ、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロシクロアルキルまたは置換ヘテロシクロアルキルから選択され、式中、Ｒ、Ａ、Ｌ_２０１、Ｍ、Ｌ_１０１、Ｚ_１０１、Ｑ_１、Ｑ_２およびＧは、第一実施形態において定義されている通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ₃₀₁ represents H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, —CH _2. - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ - diarylamino, - (C = O) - alkylamino, - (C = O) - dialkylamino, - (C = O ) -Arylamino,-(C = O) -diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or substituted heterocyclo Selected from alkyl, wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , Q ₁ , Q ₂ and G are as defined in the first embodiment.

  Other embodiments of the invention are of the formula VII and VIII, alone or in combination with a pharmaceutically acceptable carrier or excipient.

で表される化合物または医薬として許容できるこれらの塩、エステルもしくはプロドラッグであり、式中、Ｒ、Ａ、Ｌ_２０１、Ｍ、Ｌ_１０１、Ｚ_１０１、Ｑ_１、Ｑ_２およびＧは、第一実施形態において定義されている通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , Q ₁ , Q ₂ and G are the first As defined in the embodiment.

  Other embodiments of the invention are of the formula IX and X, alone or in combination with a pharmaceutically acceptable carrier or excipient.

で表される化合物または医薬として許容できるこれらの塩、エステルもしくはプロドラッグであり、式中、Ｒ、Ａ、Ｌ_２０１、Ｍ、Ｌ_１０１、Ｚ_１０１、Ｑ_１、Ｑ_２およびＧは、第一実施形態において定義されている通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , Q ₁ , Q ₂ and G are the first As defined in the embodiment.

  Representative compounds of the present invention include, but are not limited to, the following compounds according to formula XI (wherein R, ML and G are represented in each example in Table 1): Table 1).

  Representative compounds of the present invention include, but are not limited to, the following compounds according to Formula XII (wherein R, ML and G are represented in each example in Table 2): Table 2) is also included.

  Representative compounds of the present invention include, but are not limited to, the following compounds according to Formula XIII (wherein R, ML and G are represented in each example in Table 3): Table 3) is also included.

本発明の代表的な化合物として、これらに限定されないが、式ＸＩＶ（式中、Ｒ、Ｍ−ＬおよびＧは、表４における各実施例で表されている。）に従った以下の化合物（表４）も挙げられる。

Representative compounds of the present invention include, but are not limited to, the following compounds according to formula XIV (wherein R, ML and G are represented in each example in Table 4): Table 4) is also included.

  The invention also features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.

  The compounds of the invention can be administered as a single active pharmaceutical agent or used in combination with one or more agents to treat or prevent symptoms associated with hepatitis C infection or HCV infection. Other agents that are administered in combination with one or more compounds of the invention include therapeutic agents for diseases caused by HCV infection that suppress HCV viral replication by direct or indirect mechanisms. These include host immune functions such as agents such as host immune regulators (eg, interferon alpha, pegylated interferon alpha, interferon beta, interferon gamma and CpG oligonucleotides), or inosine monophosphate dehydrogenase (eg, ribavirin) And an antiviral compound that inhibits. Also included are cytokines that regulate immune function. Also included are vaccines containing HCV antigens, or combinations of antigen adjuvants directed to HCV. Block viral protein synthesis by interfering with host cell components and inhibiting an in-sequence ribosome entry site (IRES) that initiates the translational step of HCV viral replication, or a membrane protein such as HCV P7 Also included are agents that block virion maturation and release along with agents that target the porin family. Other agents administered in combination with the compounds of the present invention include any agent or combination of agents that inhibits HCV replication by targeting viral genomic proteins involved in viral replication. These agents include, for example, nucleoside polymerase inhibitors described in WO01 90121 (A2) or US Pat. No. 6,348,587 B1 or WO0160315 or WO0132153 or benzimidazoles described in EP 1216196A1 or WO0204425, for example. Other inhibitors of HCV RNA-dependent RNA polymerase such as non-nucleoside inhibitors such as polymerase inhibitors, or inhibitors of HCV protease such as peptidomimetic inhibitors such as BILN2061, or inhibitors of HCV helicase However, it is not limited to these.

  Other agents that are administered in combination with the compounds of the present invention include any agent or combination of agents that inhibit the replication of other viruses to a co-infected individual. These agents include, for example, therapeutic agents for diseases caused by hepatitis B (HBV) infection such as adefovir, lamivudine and tenofovir, or therapeutic agents for diseases caused by human immunodeficiency virus (HIV) infection such as protease inhibitors: Ritonavir , Lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, phosamprenavir; reverse transcriptase inhibitors: zidovudine, lamivudine, didanosine, stavudine, tenofovir, zarcitabine, abacavir, efavirenz, nebipine Delavirdine, TMC-125; integrase inhibitor: L-870812, S-1360 or entry inhibitor: enfuvirtide (T-20), T-1249. But it is not limited to, et al.

  That is, one embodiment of the present invention provides an agent or compounds selected from the group consisting of a host immunomodulator and a second antiviral agent, or a combination thereof, in a therapeutically effective amount of a compound of the present invention or between compounds. RNA-containing virus comprising co-administration to a patient in need of such treatment, in combination with, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, prodrug salt, or combination thereof Directed to a method for treating or preventing an infection caused by. Examples of host immune modulators include, but are not limited to, interferon alpha, pegylated interferon alpha, interferon beta, interferon gamma, cytokines, vaccines, and vaccines including antigens and adjuvants, wherein the second antiviral agent is HCV replication is inhibited by either inhibiting host cell functions involved in viral replication or by targeting proteins in the viral genome.

  Further aspects of the invention include a therapeutically effective amount of a compound of the invention or a combination of compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, prodrug salt, or combinations thereof, Treating infections caused by RNA-containing viruses, including co-administering agents or combinations of agents that treat or reduce symptoms of HCV infection, including cirrhosis and inflammation of the liver, to patients in need of such treatment or Intended for preventive methods. Another aspect of the present invention provides a therapeutically effective amount of a compound of the present invention or a combination of compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, prodrug salt, or a combination thereof. And treating infections caused by RNA-containing viruses, including co-administering one or more agents to treat patients with diseases caused by hepatitis B (HBV) infection to patients in need of such treatment Or provide a way to prevent. Agents for treating patients with diseases caused by hepatitis B (HBV) infection may be, but are not limited to, for example, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof. Examples of RNA-containing viruses include, but are not limited to, hepatitis C virus (HCV).

  Another aspect of the present invention is to provide a therapeutically effective amount of a compound of the present invention or a combination of compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, prodrug salt, or combinations thereof. Treating infections caused by RNA-containing viruses, including co-administering one or more agents to treat patients with diseases caused by human immunodeficiency virus (HIV) infection to patients in need of such treatment Or provide a way to prevent. Agents for treating patients with diseases caused by human immunodeficiency virus (HIV) infections include, but are not limited to, ritonavir, lopinavir, indinavir, nelfumavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, phosampir Lenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any of these Can be mentioned. Examples of RNA-containing viruses include, but are not limited to, hepatitis C virus (HCV). Furthermore, the present invention provides for preparing a medicament for the treatment of infections caused by RNA-containing viruses, in particular hepatitis C virus, in patients, the compounds of the present invention or combinations of compounds or therapeutically acceptable salt forms, stereoisomerisms. Or tautomers, prodrugs, prodrug salts, or combinations thereof, and use of one or more agents selected from the group consisting of host immune modulators and second antiviral agents or combinations thereof I will provide a. Examples of host immune modulators include, but are not limited to, interferon alpha, pegylated interferon alpha, interferon beta, interferon gamma, cytokines, vaccines, and vaccines including antigens and adjuvants, wherein the second antiviral agent is HCV replication is inhibited by either inhibiting host cell functions involved in viral replication or by targeting proteins in the viral genome.

  When used in the above or in other therapies, the compound or combination of compounds of the invention is in pure form, together with one or more agents as defined herein above, or Where such forms are present, they can be used in the form of pharmaceutically acceptable salts, prodrugs, prodrug salts, or combinations thereof. Alternatively, such combinations of therapeutic agents are combined with one or more agents as defined herein above and a pharmaceutically acceptable carrier to produce a therapeutically effective amount of the compound or compound of interest. They can be administered in combination or as a pharmaceutically acceptable salt form, prodrug, or pharmaceutical composition containing a prodrug salt. Such pharmaceutical compositions can be used to inhibit the replication of RNA-containing viruses, particularly hepatitis C virus (HCV), by contacting the viruses with the pharmaceutical composition. Furthermore, such compositions are useful for the treatment or prevention of infections caused by RNA-containing viruses, particularly hepatitis C virus (HCV).

  Accordingly, a further aspect of the present invention is directed to a compound of the present invention or combinations of compounds or pharmaceutically acceptable salts, stereoisomers or tautomers, prodrugs, prodrug salts or combinations thereof, as used herein. RNA-containing viruses, particularly hepatitis C, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising one or more agents as defined above and a pharmaceutically acceptable carrier. It is directed to a method of treating or preventing an infection caused by a virus (HCV).

  When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or within a given time, or the therapeutic agents can be given as a single unit dosage form. .

  Antiviral agents contemplated for use in such combination therapy include, but are not limited to, mammals, including agents that interfere with either the host or viral machinery required for virus formation and / or replication in mammals. And agents (compounds or biologics) that are effective to inhibit virus formation and / or replication in Such agents can be selected from other anti-HCV agents; HIV inhibitors; HAV inhibitors; and HBV inhibitors.

  Other anti-HCV agents include agents that are effective in reducing or preventing the progression of hepatitis C related symptoms or disease. Such agents include, but are not limited to, immunomodulators, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase, inhibitors of other targets in the HCV life cycle, and but are not limited to ribavirin, amantadine, Other anti-HCV agents including levovirin and viramidine are included.

  Such immunomodulatory agents include agents (compounds or biologics) that are effective to enhance or enhance the immune system response in mammals. The immunomodulators include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (Merimeposib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferon pegylated interferons, and Examples include, but are not limited to, bound interferons including interferons bound to other proteins including but not limited to human albumin. Class I interferons are a group of interferons that all bind to type I receptors, including naturally and synthetically produced class I interferons, while class II interferons all bind to type II receptors. Yes. Examples of class I interferons include, but are not limited to, [α]-, [β]-, [δ]-, [ω]-and [τ] -interferons, while examples of class II interferons include Non-limiting examples include [γ] -interferon.

  Inhibitors of HCV NS3 protease include agents (compounds or biologics) that are effective in inhibiting the function of HCV NS3 protease in mammals. Inhibitors of HCV NS3 protease include, but are not limited to, WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (all by Boehringer Ingelheim), WO 02/060926, W O 03/053349, WO 03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO 2005/037214 (Intermune) and WO 2005/051980 (Schering), and VX-950 , ITMN-191 and SCH 503034.

  Inhibitors of HCV polymerase include agents (compounds or biologics) that are effective in inhibiting the function of HCV polymerase. Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors of HCV polymerase include, but are not limited to, WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO 2004/064925, WO 2004/0665367, WO 2005/080388 and WO 2006/007693 (all from Boehringer Ingelheim), WO 2005/049622 (Nihon Tobacco), WO 2005/014543 (Nihon Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/109993 (IRBM) Neogenesis), WO 03/026687 (BMS), WO 03/000254 (Nihon Tobacco) and WO 01/47883 (Japan) And the clinical candidates XTL-2125, HCV796, R-1626 and NM283.

  Other targeted inhibitors in the HCV life cycle include agents (compounds or biologics) that are effective to inhibit the formation and / or replication of HCV, other than inhibiting the function of HCV NS3 protease. Such agents can interfere with either the host or HCV viral machinery required for HCV formation and / or replication. Other target inhibitors in the HCV life cycle include, but are not limited to, agents that inhibit targets selected from entry inhibitors, helicases, NS2 / 3 proteases and intrasequence ribosome entry sites (IRES), and Agents that interfere with the function of other viral targets, including but not limited to NS5A and NS4B proteins.

  Patients may be concomitant with hepatitis C virus and one or more other viruses including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV). It can happen that there is a risk of being infected. Accordingly, combination therapies for treating such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, HAV inhibitor and HBV inhibitor are also contemplated.

  According to yet another embodiment, the pharmaceutical compositions of the present invention inhibit other targets in the HCV life cycle, including but not limited to helicases, polymerases, metalloproteases and intrasequence ribosome entry sites (IRES). Agent (s) can further be included.

  According to another embodiment, the pharmaceutical composition of the present invention may further comprise another antiviral agent, antibacterial agent, antifungal agent or anticancer agent, or immunomodulator, or another therapeutic agent.

  According to yet another embodiment, the present invention includes, but is not limited to, an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, in a viral infection such as hepatitis C infection in a subject in need of such treatment. A method of treating by administering an ester or prodrug to said subject.

  According to a further embodiment, the present invention provides a method of treating hepatitis C infection in a subject in need of such treatment by administering to said subject an effective or inhibitory amount of an anti-HCV virus pharmaceutical composition of the present invention. include.

  Additional embodiments of the present invention include methods of treating a biological sample by contacting the biological sample with a compound of the present invention.

  Also, a further aspect of the invention is a method of making a compound represented herein using any of the synthetic means depicted herein.

  Cytochrome P450 monooxygenase inhibitors used in the present invention are expected to inhibit the metabolism of the compounds of the present invention. Thus, the cytochrome P450 monooxygenase inhibitor is in an amount effective to inhibit the metabolism of the protease inhibitor. That is, the CYP inhibitor is administered in an amount that increases the bioavailability of the protease inhibitor compared to the bioavailability in the absence of the CYP inhibitor.

  In one embodiment, the present invention provides a method for improving the pharmacokinetics of a compound of the present invention. The benefits of improving the pharmacokinetics of drugs are recognized in the art (US 2004/0091527; US 2004/0152625; US 2004/0091527). Thus, one embodiment of the present invention provides a method for administering an inhibitor of CYP3A4 and a compound of the present invention. Another embodiment of the present invention includes compounds of the present invention and isozymes 3A4 (“CYP3A4”), isozyme 2C19 (“CYP2C19”), isozyme 2D6 (“CYP2D6”), isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“ Methods are provided for administering inhibitors of CYP2C9 ") or isozyme 2E1 (" CYP2E1 "). In a preferred embodiment, the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant NS3 / 4A protease can be used in the methods of the invention. These CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436), ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporine, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxyamine, fluoxetine , Nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944 and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporine and chromethiazole.

  Administration of the combination of the present invention by means of patient single package and patient package (s) of each formulation containing package inserts instructing the patient to use the present invention correctly is provided by the present invention. It will be appreciated that this is a desirable additional feature.

  According to a further aspect of the invention is a package comprising at least a guide attachment containing instructions for use of the compounds of the invention and the CYP inhibitors of the invention, and the combination of the invention. In an alternative embodiment of the invention, the pharmaceutical package further comprises one or more additional agents as described herein. The additional one or more agents can be provided in the same package or in separate packages.

  This alternative embodiment includes a single or multiple pharmaceutical formulations of each pharmaceutical component; a container containing the pharmaceutical formulation (s) during storage and prior to administration; and a method effective for treating or preventing HCV infection. Include packaging kits that patients use to treat or prevent HCV infection, including instructions for performing drug administration.

  That is, the present invention provides kits for simultaneous or sequential administration of NS3 / 4A protease inhibitors and CYP inhibitors (and optionally additional agents) of the present invention, or derivatives thereof prepared by conventional methods. Typically, such kits include, for example, a composition of each inhibitor and optionally additional agent (s) in a pharmaceutically acceptable carrier (and one or more pharmaceutical formulations) and instructions for simultaneous or sequential administration. Includes a letter.

In another embodiment, one or more dosage forms for self-administration; container means, preferably sealed, for storing the dosage forms during storage and prior to use; and the patient performs the drug administration A packaging kit containing instructions for providing is provided. The instructions are usually instructions on the package insert, label and / or other components of the kit, and the dosage form or form is as described herein. Each dosage form can be isolated from other dosage forms in individual cells or bubbles and individually contained in a metal foil-plastic laminate sheet, or the dosage form can be contained in a plastic bottle. Can be contained in a single container. The kit typically also includes means for packaging the individual kit components, ie, the dosage form, container means, and instructions for use. Such packaging means may take the form of cardboard or paper boxes, plastic or foil sachets and the like.
Definitions Listed below are definitions of various terms used to describe this invention. These definitions apply to terms used throughout this specification and claims, unless otherwise limited in specific examples, either individually or as part of a larger group.

  The term “viral infection” refers to the entry of a virus, eg, hepatitis C virus (HCV), into a cell or tissue. In general, chronic liver disease virus invasion is also associated with replication. Viral infection can be determined by measuring the viral antibody titer in a sample of body fluid, such as blood, using, for example, an enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques such as RT-PCR, direct hybrid capture assay and nucleic acid sequence based amplification. Viruses can infect organs such as the liver and cause diseases such as hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.

  The term “anticancer agent” refers to a compound or drug capable of preventing or inhibiting the progression of cancer. Examples of such agents include cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, teniposide, taxol, colchicine, cyclosporin A, phenothiazine or thioxanthene.

  The term “antifungal agent” describes compounds that can be used to treat fungal infections other than 3-AP, 3-AMP or prodrugs of 3-AP and 3-AMP according to the present invention. Used for. Antifungal agents according to the present invention include, for example, terbinafine, fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin, nystatin, tolnaftate, caspofungin, amphotericin B, liposomal amphotericin B and amphotericin B lipid complex.

  The term “antibacterial agent” is synthesized or modified in the laboratory with naturally occurring antibiotics produced by microorganisms that inhibit the growth of other microorganisms, as well as either bactericidal or bacteriostatic activity. Refers to both drugs such as β-lactam antibacterial agents, glycopeptides, macrolides, quinolones, tetracyclines and aminoglycosides. In general, if an antibacterial agent is bacteriostatic, it means that the agent essentially stops the growth of bacterial cells (but does not kill the bacteria), and if the agent is bactericidal, the agent is a bacterial It means killing the cells (and sometimes stopping the growth before killing the bacteria).

  The term “immunomodulator” refers to any substance that is meant to alter the function of a subject's humoral or cellular immune system. Such immunomodulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, corticosteroids, colony stimulating factors, chemotactic factors, and the like.

The term “C ₁ -C ₆ alkyl” or “C ₁ -C ₈ alkyl” and the like as used herein refers to between 1 and 6 or between 1 and 8 carbon atoms. Each represents a saturated straight or branched chain hydrocarbon group. Examples of C ₁ -C ₆ alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, Examples of C ₁ -C ₈ alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, An octyl group is mentioned.

The terms “C ₂ -C ₆ alkenyl” or “C ₂ -C ₈ alkenyl” and the like, as used herein, denote a group derived from a hydrocarbon component, wherein the hydrocarbon component is It has at least one carbon-carbon double bond and contains 2 to 6 or 2 to 8 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The terms “C ₂ -C ₆ alkynyl” or “C ₂ -C ₈ alkynyl” and the like, as used herein, denote a group derived from a hydrocarbon component, wherein the hydrocarbon component is It has at least one carbon-carbon triple bond and contains 2 to 6, or 2 to 8 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The terms “C ₃ -C ₈ -cycloalkyl” or “C ₃ -C ₁₂ -cycloalkyl” and the like as used herein are derived from monocyclic or polycyclic saturated carbocycles. Wherein the saturated carbocyclic compound has 3 to 8, or 3 to 12 ring atoms, respectively. Examples of C ₃ -C ₈ -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl, and examples of C ₃ -C ₁₂ -cycloalkyl include, but are not limited to, Although not mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl and bicyclo [2.2.2] octyl.

The terms “C ₃ -C ₈ -cycloalkenyl” or “C ₃ -C ₁₂ -cycloalkenyl” and the like, as used herein, are monocyclic having at least one carbon-carbon double bond, or 1 represents a group derived from a polycyclic carbocyclic compound, wherein the carbocyclic compound has 3 to 8, or 3 to 12 ring atoms, respectively. Examples of C ₃ -C ₈ -cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, and examples of C ₃ -C ₁₂ -cycloalkenyl include Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

  The term “aryl” as used herein includes, but is not limited to, one or two aromatic rings having one or two aromatic rings, including phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, and the like. Refers to a bicyclic carbocyclic ring system.

The term “arylalkyl” as used herein refers to a C ₁ -C ₃ alkyl residue or a C ₁ -C ₆ alkyl residue attached to an aryl ring. Examples include but are not limited to benzyl, phenethyl and the like.

  The term “heteroaryl” as used herein refers to a monocyclic, bicyclic or at least one ring atom having 5 to 10 ring atoms selected from S, O and N Refers to a tricyclic aromatic group or aromatic ring, where any N or S contained within the ring can be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and the like Can be mentioned.

The term “heteroarylalkyl” as used herein refers to a C ₁ -C ₃ alkyl residue or a C ₁ -C ₆ alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl and pyrimidinylethyl.

The term “substituted” as used herein includes, but is not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO ₂ , —CN, — NH _{2, N 3,} protected amino, alkoxy, thioalkoxy, oxo, - halo _-C 1 _{-C 12} - alkyl, - halo _-C 2 _{-C 12} - alkenyl, - halo _-C 2 _{-C 12} - alkynyl, - halo _-C 3 _{-C 12} - cycloalkyl, _-NH-C 1 _{-C 12} - alkyl, _-NH-C 2 _{-C 12} - alkenyl, _-NH-C 2 _{-C 12} - alkynyl, _{-NH-C 3} - C ₁₂ - cycloalkyl, -NH- aryl, -NH- heteroaryl, -NH- heterocycloalkyl, - dialkylamino, - diarylamino, - diheteroarylamino, _-O-C 1 -C ₁₂ - alkyl, _-O-C 2 _{-C 12} - alkenyl, _-O-C 2 _{-C 12} - alkynyl, _-O-C 3 _{-C 12} - cycloalkyl, -O- aryl, -O- heteroaryl, - O- _{heterocycloalkyl, -C (O) -C 1 -C} 12 - _{alkyl, -C (O) -C 2 -C} 12 - _{alkenyl, -C (O) -C 2 -C} 12 - alkynyl, -C _{(O) -C} 3 -C ₁₂ - cycloalkyl, -C (O) - aryl, -C (O) - heteroaryl, -C (O) - _{heterocycloalkyl, -CONH 2, -CONH-C 1} - C ₁₂ - alkyl, _-CONH-C 2 _{-C 12} - alkenyl, _-CONH-C 2 _{-C 12} - alkynyl, _-CONH-C 3 _{-C 12} - cycloalkyl, -CONH- aryl, -CONH- heteroarylene , -CONH- _{heterocycloalkyl,} -OCO _{2 -C} 1 -C ₁₂ - _alkyl, -OCO _{2 -C 2} -C ₁₂ - _alkenyl, -OCO _{2 -C 2} -C ₁₂ - alkynyl, -OCO ₂ -C ₃ -C ₁₂ - cycloalkyl, --OCO ₂ - aryl, --OCO ₂ - heteroaryl, --OCO ₂ - _{heterocycloalkyl, -OCONH 2, -OCONH-C 1} -C 12 - alkyl, _-OCONH-C 2 -C ₁₂ - alkenyl, _-OCONH-C 2 _{-C 12} - alkynyl, _-OCONH-C 3 _{-C 12} - cycloalkyl, -OCONH- aryl, -OCONH- heteroaryl, -OCONH- heterocycloalkyl, -NHC (O) -C ₁ -C ₁₂ - _{alkyl, -NHC (O) -C 2 -C} 12 - alkenyl, -N _{HC (O) -C 2 -C 12} - _{alkynyl, -NHC (O) -C 3 -C} 12 - cycloalkyl, -NHC (O) - aryl, -NHC (O) - heteroaryl, -NHC (O) - _{heterocycloalkyl,} -NHCO _{2 -C} 1 -C ₁₂ - _alkyl, -NHCO _{2 -C 2} -C ₁₂ - _alkenyl, -NHCO _{2 -C 2} -C ₁₂ - _alkynyl, -NHCO _{2 -C} 3 -C ₁₂ - cycloalkyl, -NHCO ₂ - aryl, -NHCO ₂ - heteroaryl, -NHCO ₂ - _{heterocycloalkyl, -NHC (O) NH 2,} -NHC (O) NH-C 1 -C 12 - alkyl, -NHC _{(O) NH-C 2 -C} 12 - _{alkenyl, -NHC (O) NH-C} 2 -C 12 - _{alkynyl, -NHC (O) NH-C} 3 -C 12 - Sik Alkyl, -NHC (O) NH- aryl, -NHC (O) NH- heteroaryl, -NHC (O) NH- _{heterocycloalkyl, NHC (S) NH 2,} -NHC (S) NHC 1 -C ₁₂ - _{alkyl, -NHC (S) NH-C} 2 -C 12 - _{alkenyl, -NHC (S) NH-C} 2 -C 12 - _{alkynyl, -NHC (S) NH-C} 3 -C 12 - cycloalkyl, -NHC (S) NH- aryl, -NHC (S) NH- heteroaryl, -NHC (S) NH- _{heterocycloalkyl, -NHC (NH) NH 2,} -NHC (NH) NH-C 1 -C 12 - _{alkyl, -NHC (NH) NH-C} 2 -C 12 - _{alkenyl, -NHC (NH) NH-C} 2 -C 12 - _{alkynyl, -NHC (NH) NH-C} 3 -C 12 - Shikuroa Alkyl, -NHC (NH) NH- aryl, -NHC (NH) NH- heteroaryl, -NHC (NH) NH- _{heterocycloalkyl, -NHC (NH) -C 1 -C} 12 - alkyl, -NHC (NH ) _-C 2 _{-C 12} - _{alkenyl, -NHC (NH) -C 2 -C} 12 - _{alkynyl, -NHC (NH) -C 3 -C} 12 - cycloalkyl, -NHC (NH) - aryl, -NHC ( NH) - heteroaryl, -NHC (NH) - _{heterocycloalkyl, -C (NH) NH-C} 1 -C 12 - _{alkyl, -C (NH) NH-C} 2 -C 12 - alkenyl, -C (NH ) _NH-C 2 _{-C 12} - _{alkynyl, -C (NH) NH-C} 3 -C 12 - cycloalkyl, -C (NH) NH- aryl, -C (NH) NH- heteroaryl, - (NH) NH- _{heterocycloalkyl, -S (O) -C 1 -C} 12 - _{alkyl, -S (O) -C 2 -C} 12 - _{alkenyl, -S (O) -C 2 -C} 12 - alkynyl _{, -S (O) -C 3 -C} 12 - cycloalkyl, -S (O) - aryl, -S (O) - heteroaryl, -S (O) - heterocycloalkyl _-SO 2 _NH 2, _{-SO 2 NH-C} 1 _{-C 12} - _{alkyl, -SO 2 NH-C 2 -C} 12 - _{alkenyl, -SO 2 NH-C 2 -C} 12 - _{alkynyl, -SO 2 NH-C 3 -C} 12 - cycloalkyl , _-SO 2 NH- aryl, _-SO 2 NH- heteroaryl, _-SO 2 NH- _{heterocycloalkyl,} -NHSO _{2 -C} 1 -C ₁₂ - _alkyl, -NHSO _{2 -C 2} -C ₁₂ - alkenyl, - NH O ₂ -C ₂ -C ₁₂ - _alkynyl, -NHSO _{2 -C} 3 -C ₁₂ - cycloalkyl, -NHSO ₂ - aryl, -NHSO ₂ - heteroaryl, -NHSO ₂ - heterocycloalkyl, _-CH 2 NH _{2 , -CH 2 SO 2 CH 3,} - aryl, - arylalkyl, - heteroaryl, - heteroarylalkyl, - _{heterocycloalkyl,} -C 3 _{-C 12} - cycloalkyl, polyalkoxyalkyl, polyalkoxy, - methoxymethoxy , - _{methoxyethoxy, -SH, -S-C 1 -C} 12 - alkyl, _-S-C 2 _{-C 12} - alkenyl, _-S-C 2 _{-C 12} - alkynyl, _-S-C 3 _{-C 12} - Cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, methylthiome Le or -L'-R '(wherein, L' _is a C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene, R 'is aryl, heteroaryl, heterocycle a _C 3 _{-C 12} cycloalkyl or _C 3 _{-C 12} cycloalkenyl. ), And one, two, or three or more hydrogen atoms are independently replaced. It is understood that aryl, heteroaryl, alkyl, and the like may be further substituted. In some examples, each substituent in the substituted component is optionally substituted with one or more additional groups, each group being -F, -Cl, -Br, -I,- _OH, -NO 2, are independently selected from -CN or -NH _2. When there are at least two hydrogen atom substitutions with a substituent, the two substituents can be taken together to form a cycloalkyl, cycloalkenyl, or heterocycle.

  According to the present invention, any of the aryl, substituted aryl, heteroaryl, and substituted heteroaryl described herein can be any aromatic group. The aromatic group may be substituted or unsubstituted.

  It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl moiety described herein may be an aliphatic group, an alicyclic group, or a heterocyclic group. An “aliphatic group” may contain any combination of carbon, hydrogen, halogen, oxygen, nitrogen or other atoms, optionally with one or more units of unsaturated bonds, such as double and It is a non-aromatic component that may contain triple bonds. An aliphatic group may be straight chained, branched or cyclic and contains between about 1 and about 24 carbon atoms, more usually between about 1 and about 12 carbon atoms. Is preferred. In addition to the aliphatic hydrocarbon group, the aliphatic group includes, for example, polyalkoxyalkyl such as polyalkylene glycol, polyamine and polyimine. Such aliphatic groups may be further substituted. It is understood that an aliphatic group can be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups described herein.

  The term “alicyclic” as used herein refers to a group derived from a monocyclic or polycyclic saturated carbocyclic compound. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.

  The terms “heterocycloalkyl” and “heterocycle” can be used interchangeably and are non-aromatic 3-, 4-, 5-, 6- or 7-membered rings or bi- or tri-rings. Refers to a fused system of formula groups, wherein (i) each ring contains between 1 and 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and (ii) each 5 membered The ring has 0 to 1 double bonds, each 6-membered ring has 0 to 2 double bonds, and (iii) nitrogen and sulfur heteroatoms can optionally be oxidized ( iv) The nitrogen heteroatom may optionally be quaternized, (v) any of the above rings can be fused to a benzene ring, and (vi) the remaining ring atoms are optionally oxo substituted. It can be any carbon atom. Exemplary heterocycloalkyl groups include, but are not limited to, [1,3] dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazo And lysinyl, quinoxalinyl, pyridazinonyl and tetrahydrofuryl. Such heterocyclic groups may be further substituted and substituted heterocycles.

  In various embodiments of the invention, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are monovalent, divalent, or polyvalent. It is clear that it is intended. Therefore, an alkylene group, an alkenylene group and an alkynylene group, a cycloalkylene group, a cycloalkenylene group, a cycloalkynylene group, an arylalkylene group, a heteroarylalkylene group and a heterocycloalkylene group should be included in the above definition, and the present invention Can be applied to give an appropriate value to

  The term “hydroxy-activating group” as used herein is known in the art for activating a hydroxy group to leave during a synthetic procedure, such as in a substitution or removal reaction. Refers to unstable chemical components. Examples of hydroxy activating groups include, but are not limited to, mesylate, tosylate, triflate, p-nitrobenzoate and phosphonate.

  The term “activated hydroxy” as used herein includes hydroxy as defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups. Refers to a hydroxy group activated with an activating group.

  The term “protected hydroxy” as used herein is protected with a hydroxy protecting group as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups. Refers to a modified hydroxy group.

  The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

  The compounds described herein contain one or more asymmetric centers and, therefore, in terms of enantiomers, diastereomers, and absolute stereochemistry, as (R)-or (S)- Or other stereoisomeric forms that can be defined as (D)-or (L)-with respect to amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above or by resolving racemic mixtures. The resolution can be carried out in the presence of a resolution agent by chromatography or iterative crystallization known to those skilled in the art or a combination of these techniques. Further details on partitioning can be found in Jacques et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). The compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, the compounds may include both E and Z geometric isomers. Intended. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing in the present invention is selected for convenience only and is not intended to design a particular configuration unless stated herein, and therefore is herein described as a transformer. The carbon-carbon double bond indicated as appropriate in may be cis, trans, or a mixture of the two in any proportion.

  The term “subject” as used herein refers to a mammal. Subjects thus refer to, for example, dogs, cats, horses, cows, pigs and guinea pigs. Preferably, the subject is a human. Where the subject is a human, the subject may be referred to herein as a patient.

  As used herein, the term “pharmaceutically acceptable salt” is in contact with human and lower animal tissues that do not have undue toxicity, irritation, and allergic response within the scope of sound medical judgment. Refers to a salt of a compound formed by the method of the invention that is suitable for use and is commensurate with a reasonable effect / risk ratio. Pharmaceutically acceptable salts are well known in the art.

The term “hydroxy protecting group” as used herein refers to labile chemical moieties known in the art for protecting hydroxy groups against undesired reactions during synthetic procedures. Point to. After the synthetic procedure (s), the hydroxy protecting group as described herein can be selectively removed. Hydroxy protecting groups known in the art are described in T.W. H. Greene and P.M. G. S. M.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t- Butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, Benzyl, paramethoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, para -Toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or —C (O) CH ₃ ), benzoyl (Bz or —C (O) C ₆ H ₅ ) and trimethylsilyl (TMS or —Si (CH ₃ ) _3. ). Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base functionality with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts such as inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, maleic acid, tartaric acid, Examples include salts of amino groups formed with organic acids such as citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, Camphor acid, camphor sulfonic acid, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, semi Sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malon Acid salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, Luminate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, Examples thereof include tartrate, thiocyanate, p-toluenesulfonate, undecanoate and valerate. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, when appropriate, non-toxic ammonium, quaternary ammonium, and halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, 1 to 6 carbon atoms And cations of amines formed using counterions such as alkyl, sulfonate and aryl sulfonates having

  The term “amino protecting group” as used herein refers to labile chemical moieties known in the art for protecting amino groups against undesired reactions during synthetic procedures. Point to. After the synthetic procedure (s), the amino protecting group as described herein can be selectively removed. Amino protecting groups known in the art include T.I. H. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

  As used herein, the term “pharmaceutically acceptable ester” refers to a compound formed by a method of the invention that hydrolyzes in vivo and is readily degraded in the human body to the parent compound or the compound. Include those that leave the salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, wherein each alkyl or alkenyl component contains 6 It is advantageous to have the following carbon atoms: Examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethyl succinate.

  The term “pharmaceutically acceptable prodrug” as used herein refers to human and lower animal tissues that have excessive toxicity, irritation, and allergic responses, etc., within the scope of sound medical judgment. Compounds formed by the process of the present invention that are suitable for contact use, are commensurate with a reasonable effect / risk ratio, are effective for their intended use, and are zwitterionic forms of the compounds of the present invention where possible Refers to prodrugs. “Prodrug” as used herein means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to yield any compound represented by the formula of the invention. . For example, Bundgaard (Editor), Design of Prodrugs, Elsevier (1985); Widder et al. (Editor), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgard et al. Prodrugs, Textbook of Drug Design and Development, Chapter 5, pages 113-191 (1991); Bundgaard et al., Journal of Drug Reviews, Vol. 1-38; of Pharmaceutical Sciences, 77 Volume: 285 pages or less than the reference (1988); Higuchi and Stella (Edit) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975 years); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology ", John Wiley and Sons, Ltd. As discussed in (2002), various forms of prodrugs are known in the art.

  The term “acyl” includes residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyl include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxyacetyl, and the like.

  The term “aprotic solvent” as used herein refers to a solvent that is relatively inert to proton activity, ie, does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, such as halogenated hydrocarbons such as methylene chloride, ethylene chloride and chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and diethyl ether And ethers such as bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may vary for a particular compound and reaction conditions, depending on factors such as, for example, reagent solubility, reagent reactivity, and preferred temperature range. It may be preferable. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized studies, such as Organic Solvents Physical Properties and Methods of Purification, 4th edition, John A. et al. Edited by Riddick et al., Volume II, the Technologies of Chemistry Series, John Wiley & Sons, NY, 1986.

  The terms “protic organic solvent” or “protic solvent” as used herein tend to provide protons, such as alcohols such as methanol, ethanol, propanol, isopropanol, butanol and t-butanol. Refers to a solvent. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may vary for a particular compound and reaction conditions, depending on factors such as, for example, reagent solubility, reagent reactivity, and preferred temperature range. It may be preferable. Further discussion of protic solvents can be found in organic chemistry textbooks or specialized studies, such as Organic Solvents Physical Properties and Methods of Purification, 4th edition, John A. et al. Edited by Riddick et al., Volume II, the Technologies of Chemistry Series, John Wiley & Sons, NY, 1986.

  The combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, has sufficient stability to allow for manufacture and is detailed herein to maintain compound integrity for a sufficient period of time. Refers to a compound that is useful for the intended purpose (eg, therapeutic or prophylactic administration to a subject).

  The synthetic compound can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. In addition, the various synthetic steps can be performed in an alternative order or sequence to provide the desired compound. Solvents, temperatures, reaction times, etc. represented herein are for illustrative purposes only, and the desired crosslinked macrocycle product of the present invention can be produced by changing the reaction conditions. Synthetic chemical variations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are described in, for example, R.A. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons (1991); Fieser and M.M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Examples include those described in Edited by Packete, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

  The compounds of the present invention can be modified by the addition of various functional groups through the synthetic means depicted herein to enhance selective biological properties. These modifications increase biological penetration into certain biological systems (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility, and allow administration by injection And changing metabolism and changing excretion rate.

Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or any type of formulation aid. To do. Some examples of substances that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate and derivatives thereof; Powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil and cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; And esters such as ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginate; pyrogen-free water; isotonic saline; Ringer's solution; And other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, fragrances and fragrances, stored The ingredients and antioxidants can also be present in the composition according to the judgment of the prescriber. The pharmaceutical composition of the present invention is administered to humans and other animals by oral administration, rectal administration, parenteral administration, intracisternal administration, intravaginal administration, intraperitoneal administration, topical administration (by powder, ointment or infusion) ), Buccal administration, or oral or nasal spray.

  The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, Oral administration or administration by injection is preferred. The pharmaceutical composition of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some examples, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein is subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial. Include injection or infusion techniques.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers such as fatty acid esters, and mixtures thereof can be included. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.

  Injectable preparations, for example, sterile injectable aqueous or oil suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. S. P. And isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  The injectable formulation is, for example, a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed by filtration through a bacteria-retaining filter or in sterile water or other sterile injectable medium prior to use. Can be sterilized by incorporating.

  In order to prolong the effect of the drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material that is poorly water soluble. The absorption rate of the drug then depends on the dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil medium. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration are cocoa butter, polyethylene glycols or suppository waxes that are solid at ambient temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity to release the active compound Suppositories that can be prepared by mixing a compound of the present invention with a suitable nonirritating excipient or carrier such as, are preferred.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound comprises sodium citrate or dicalcium phosphate and / or a) a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) eg carboxymethylcellulose, alginate Binders such as gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) Dissolution retardants such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) kaolin and bentonite At least one inert pharmaceutically acceptable excipient, such as an absorbent such as soil, and i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof Mixed with carrier. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents.

  Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycols.

  The active compound may be in microencapsulated form with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. it can. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as usual practice. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents. These can optionally contain opacifiers, even if they are compositions that release only the active ingredient (s) or, optionally, in a delayed manner, preferentially to a specific part of the intestinal tract. Good. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also considered to be within the scope of this invention.

  Ointments, pastes, creams and gels, in addition to the active compounds according to the invention, contain animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, Excipients such as talc and zinc oxide, or mixtures thereof can be included.

  Powders and sprays can contain, in addition to a compound of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of allowing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Antiviral Activity The inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg / Kg to about 500 mg / Kg, alternatively from about 1 to about 50 mg / Kg. Inhibitory amounts or doses will vary depending on the route of administration as well as the possibility of co-use with other agents.

  In accordance with the method of treatment of the present invention, viral infection is achieved in a subject, such as a human or lower mammal, in an amount and duration necessary to achieve a desired result, an effective or inhibitory amount of an anti-hepatitis C virus. Or is treated or prevented by administering to a subject. An additional method of the invention is the treatment of a biological sample with an amount and time of an inhibitory amount of a compound of the composition of the invention necessary to achieve the desired result.

  The term “anti-hepatitis C virus effective amount” of a compound of the invention, as used herein, reduces viral load in a biological sample or subject (eg, at least 10%, preferably at least 50 %, More preferably at least 80%, and most preferably at least 90% or 95% of the amount of compound sufficient to provide a reduction in viral load). As is well understood in the medical arts, an effective amount of an anti-hepatitis C virus compound of the present invention is a reasonable effect / risk ratio applicable to any medical treatment.

  The term “inhibitory amount” of a compound of the invention reduces hepatitis C viral load in a biological sample or subject (eg, at least 10%, preferably at least 50%, more preferably at least 80%, and most Preferably an amount sufficient to result in a reduction in viral load of at least 90% or 95%. When said inhibitory amount of a compound of the invention is administered to a subject, it is understood that this is a reasonable effect / risk ratio applicable to any medical treatment as determined by a physician. The term “biological sample (s)” as used herein refers to a substance derived from an organism intended for administration to a subject. Examples of biological samples include, but are not limited to, blood and this component such as plasma, platelets and blood cell subpopulations; organs such as kidney, liver, heart and lung; sperm and egg; bone marrow and this Components; or stem cells. Accordingly, another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.

  If necessary to improve the condition of the subject, a maintenance amount of a compound, composition or combination of the invention may be administered. Thereafter, the dose or frequency of administration or both can be reduced to a level where the improved condition is retained as a function of symptoms if symptoms are alleviated to the desired level, and treatment should end. The subject, however, may require long-term intermittent treatment for any recurrence of disease symptoms.

  It will be understood, however, that the total daily dosage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient is the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, gender of the patient Well-known in the medical arts, such as: the time of administration, route of administration and excretion rate of the particular compound used; duration of treatment; and drugs used in combination with or concurrently with the particular compound used; Depends on various factors, including the factors.

  The total daily inhibitory dose of a compound of the invention administered to a subject in single or divided doses is, for example, an amount of 0.01 to 50 mg / kg body weight, or more usually 0.1 to 25 mg / kg body weight It may be. Single dose compositions can contain such amounts, or about the quantities thereof, that constitute a daily dose. In general, a treatment regimen according to the present invention comprises administration of about 10 mg to about 1000 mg of the compound (s) of the present invention per day in single or multiple doses to a patient in need of such treatment.

  Unless defined otherwise, all technical and scientific terms used herein are consistent with the meaning commonly known to one of ordinary skill in the art. All publications, patents, published patent applications and other references mentioned herein are hereby incorporated by reference in their entirety.

Abbreviations The abbreviations used in the description of the scheme and the following examples are as follows.
ACN is acetonitrile,
BME is 2-mercaptoethanol,
BOP is benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate,
COD is cyclooctadiene,
DAST is diethylaminosulfur trifluoride,
DABCYL is 6- (N-4′-carboxy-4- (dimethylamino) azobenzene) -aminohexyl-1-O- (2-cyanoethyl)-(N, N-diisopropyl) -phosphoramidite,
DCM is dichloromethane,
DIAD is diisopropyl azodicarboxylate,
DIBAL-H is diisobutylaluminum hydride,
DIEA is diisopropylethylamine,
DMAP is N, N-dimethylaminopyridine,
DME is ethylene glycol dimethyl ether,
DMEM is Dulbecco's modified Eagle medium,
DMF is N, N-dimethylformamide,
DMSO is dimethyl sulfoxide,
DUPHOS is

ＥＤＡＮＳは５−（２−アミノ−エチルアミノ）−ナフタレン−１−スルホン酸、
ＥＤＣＩまたはＥＤＣは、１−（３−ジエチルアミノプロピル）−３−エチルカルボジイミドヒドロクロリド、
ＥｔＯＡｃは酢酸エチル、
ＨＡＴＵはＯ（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロホスフェート、
Ｈｏｖｅｙｄａ’ｓ Ｃａｔ．はジクロロ（ο−イソプロポキシフェニルメチレン）（トリシクロヘキシルホスフィン）ルテニウム（ＩＩ）、
ＫＨＭＤＳはカリウムビス（トリメチルシリル）アミドであり、
Ｍｓはメシル、
ＮＭＭはＮ−４−メチルモルホリン、
ＰｙＢｒＯＰはブロモ−トリ−ピロリジノ−ホスホニウムヘキサフルオロホスフェート、
Ｐｈはフェニル、
ＲＣＭは閉環メタセシス、
ＲＴは逆転写、
ＲＴ−ＰＣＲは逆転写−ポリメラーゼ連鎖反応、
ＴＥＡはトリエチルアミン、
ＴＦＡはトリフルオロ酢酸、
ＴＨＦはテトラヒドロフラン、
ＴＬＣは薄層クロマトグラフィー、
ＴＰＰまたはＰＰｈ_３は、トリフェニルホスフィン、
ｔＢＯＣまたはＢｏｃは、ｔｅｒｔ−ブチルオキシカルボニル、および
キサントホスは４，５−ビス−ジフェニルホスファニル−９，９−ジメチル−９Ｈ−キサンテンである。

EDANS is 5- (2-amino-ethylamino) -naphthalene-1-sulfonic acid,
EDCI or EDC is 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride,
EtOAc is ethyl acetate,
HATU is O (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate;
Hoveyda's Cat. Is dichloro (ο-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (II),
KHMDS is potassium bis (trimethylsilyl) amide,
Ms is Messil,
NMM is N-4-methylmorpholine,
PyBrOP is bromo-tri-pyrrolidino-phosphonium hexafluorophosphate,
Ph is phenyl,
RCM is ring-closing metathesis,
RT is reverse transcription,
RT-PCR is reverse transcription-polymerase chain reaction,
TEA is triethylamine,
TFA is trifluoroacetic acid,
THF is tetrahydrofuran,
TLC is thin layer chromatography,
TPP or PPh ₃ is triphenylphosphine,
tBOC or Boc is tert-butyloxycarbonyl, and xanthophos is 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.

Synthetic Methods The compounds and methods of the present invention will be better understood in the context of the following synthetic schemes illustrating how the compounds of the present invention may be prepared, but these are intended to be exemplary only and It is not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including without limitation those related to the chemical structures, substituents, derivatives and / or methods of the present invention, are It may be made without departing from the spirit of the invention and the appended claims.

ＨＣＶプロテアーゼ阻害剤としてフッ素化大環状化合物を調製するための一般的方法を、スキーム１に概略する。大環状中心核のカルボン酸１−１を、ＨＡＴＵなどのカップリング剤を用いてジフルオロメチルＰ１化合物１−２とカップリングして、エステル１−４を生成し、これを酸１−５に変換した。酸１−４からスルホンアミド１−６へのさらなる転換は、ＣＤＩ／塩基／シクロプロピルスルホンアミドを使用することにより達成される。別法として、化合物１−１とジフルオロメチルＰ１−Ｐ１’１−３とのカップリングにより、化合物１−６が直接得られる。化合物１−７および１−８は、それぞれ対応する不飽和親化合物の水素化から調製される。

A general method for preparing fluorinated macrocycles as HCV protease inhibitors is outlined in Scheme 1. Coupling the carboxylic acid 1-1 of the macrocyclic central core with the difluoromethyl P1 compound 1-2 using a coupling agent such as HATU to produce the ester 1-4, which is converted to the acid 1-5 did. Further conversion of acid 1-4 to sulfonamide 1-6 is achieved by using CDI / base / cyclopropylsulfonamide. Alternatively, compound 1-6 is obtained directly by coupling of compound 1-1 with difluoromethyl P1-P1′1-3. Compounds 1-7 and 1-8 are each prepared from the hydrogenation of the corresponding unsaturated parent compound.

大環状中心核の化合物１−１は、通常、触媒としてＲｕ誘導体を使用する前駆体化合物２−１の閉環メタセシス、続いてスキーム２に示されている通りの塩基性加水分解により調製される。

Macrocyclic core compound 1-1 is typically prepared by ring-closing metathesis of precursor compound 2-1 using a Ru derivative as a catalyst, followed by basic hydrolysis as shown in Scheme 2.

式２−１で表される様々な大環状中心核の化合物は、Ｂｏｃ−Ｌ−ヒドロキシプロリンメチルエステル、対応するアミノ酸誘導体およびＸ−Ｙ−Ｗで表される中間体から作られる。大環状中心核の化合物を合成するための一般的合成戦略を、スキーム３に例示する。

Various macrocyclic central core compounds represented by Formula 2-1 are made from Boc-L-hydroxyproline methyl ester, the corresponding amino acid derivative and an intermediate represented by XYW. A general synthetic strategy for synthesizing compounds with a macrocyclic core is illustrated in Scheme 3.

大環状中心核の化合物の調製を、スキーム４にさらに例示する。化合物４−１がヒドロキシアミンと反応することにより、オキシム４−２を生成し、これを塩基性条件下においてプロリン誘導体４−３とカップリングさせて、化合物４−４が得られる。鈴木またはＳｔｉｌｌｅ式反応を介した後続のビニル化により、化合物４−５を生成した。Ｂｏｃ基の脱保護、それに続くｔｅｒｔ．−ロイシン誘導体とのカップリングにより、化合物４−６が得られ、これをさらに脱保護し、対応するクロロホルメートと反応させて、メタセシス前駆体４−７を生成した。閉環メタセシスにより大環状中心核のエステル４−８を生成し、これを加水分解して、大環状中心核の酸４−９（即ち式１−１）を得た。

The preparation of the macrocyclic core compound is further illustrated in Scheme 4. Compound 4-1 reacts with hydroxyamine to produce oxime 4-2, which is coupled with proline derivative 4-3 under basic conditions to give compound 4-4. Subsequent vinylation via Suzuki or Stille reaction produced compound 4-5. Deprotection of the Boc group, followed by tert. -Coupling with a leucine derivative gave compound 4-6, which was further deprotected and reacted with the corresponding chloroformate to produce metathesis precursor 4-7. Macrocyclic central nucleus ester 4-8 was produced by ring-closing metathesis and hydrolyzed to give macrocyclic central core acid 4-9 (ie Formula 1-1).

ジフルオロメチルＰ１アミノ酸エステル（１−２）の合成を、スキーム５に示す。モノＢｏｃアミノ酸エステル５−１を、ビスＢｏｃアミノ酸エステル５−２としてさらに保護した。化合物５−２の酸化的開裂によりアルデヒド５−３が得られ、これを次いで、三フッ化ジエチルアミノ硫黄（ＤＡＳＴ）などの三フッ化アミノ硫黄誘導体を使用してジフルオロメチル化合物５−４に変換した。ＨＣｌを使用する５−４の脱保護により、所望のジフルオロメチルＰ１化合物１−２が得られた。

Synthesis of difluoromethyl P1 amino acid ester (1-2) is shown in Scheme 5. Mono Boc amino acid ester 5-1 was further protected as bis Boc amino acid ester 5-2. Oxidative cleavage of compound 5-2 gave aldehyde 5-3, which was then converted to difluoromethyl compound 5-4 using an aminosulfur trifluoride derivative such as diethylaminosulfur trifluoride (DAST). . Deprotection of 5-4 using HCl gave the desired difluoromethyl P1 compound 1-2.

スキーム６により、ジフルオロメチルＰ１スルホンアミド誘導体（１−３）の合成を記載する。化合物５−２の加水分解により酸６−１を生成し、これを、ＣＤＩ／ＲＳＯ_２ＮＨ_２／ＤＢＵまたはＥＤＣＩ／ＤＭＡＰ／ＲＳＯ_２ＮＨ_２を使用して６−２に変換した。６−２の脱保護により、所望のジフルオロメチルＰ１スルホンアミド中間体１−３を得た。

Scheme 6 describes the synthesis of difluoromethyl P1 sulfonamide derivative (1-3). Hydrolysis of compound 5-2 yielded acid 6-1 which was converted to 6-2 using CDI / RSO ₂ NH ₂ / DBU or EDCI / DMAP / RSO ₂ NH ₂ . Deprotection of 6-2 gave the desired difluoromethyl P1 sulfonamide intermediate 1-3.

  All documents cited herein, whether in print, electronic, computer readable storage media or other forms, are not limited to abstracts, articles, journals, literature, textbooks, papers, the Internet All of these contents are incorporated by reference, including websites, databases, patents and patent publications.

  The compounds and methods of this invention will be better understood in the context of the following examples. These are intended for illustration only and are not intended to limit the scope of the present invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and include, without limitation, those related to the chemical structure, substituents, derivatives, formulations and / or methods of the present invention. May be made without departing from the spirit of the invention and the scope of the appended claims.

Example 1
A compound of formula XI wherein:

］

]

  Step 1A

化合物１Ａ１（０．５ｇ、１．９３ｍｍｏｌ）、ヒドロキシアミン塩酸塩（０．６７ｇ、５当量）およびメタノール（１２ｍ）の混合物を、還流下で５時間加熱し、室温に冷却し、ＥｔＯＡｃで希釈し、ＮａＨＣＯ３水溶液、ブラインで洗浄し、脱水させ（ＭｇＳＯ４）、濃縮乾固させて、化合物１Ａ（０．４６ｇ）が得られ、次のステップで直接使用した。

A mixture of compound 1A1 (0.5 g, 1.93 mmol), hydroxyamine hydrochloride (0.67 g, 5 eq) and methanol (12 m) was heated at reflux for 5 hours, cooled to room temperature and diluted with EtOAc. , Washed with aqueous NaHCO3, brine, dried (MgSO4) and concentrated to dryness to give compound 1A (0.46 g), which was used directly in the next step.

  Step 1B

化合物１Ａ（０．４５８ｇ、１．６７ｍｍｏｌ）、化合物１Ｂ１（１．８４ｍｍｏｌ）のＤＭＦ（４ｍｌ）中溶液に、炭酸セシウム（０．９１ｇ、２．７９ｍｍｏｌ）を添加した。生じた混合物を５０℃で２２時間撹拌し、室温に冷却し、ＥｔＯＡｃで希釈し、水、ブライン（３×）で洗浄し、脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝１：０から４：１）により精製して、１Ｂ（０．７５ｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ５０１．３０、５０３．２８（Ｍ＋Ｈ）；５２３．２０、５２５．２０（Ｍ＋Ｎａ）。

To a solution of compound 1A (0.458 g, 1.67 mmol), compound 1B1 (1.84 mmol) in DMF (4 ml) was added cesium carbonate (0.91 g, 2.79 mmol). The resulting mixture was stirred at 50 ° C. for 22 hours, cooled to room temperature, diluted with EtOAc, washed with water, brine (3 ×), dried (MgSO 4) and concentrated in vacuo, and the residue was chromatographed. Purification by (hexane / EtOAC = 1: 0 to 4: 1) produced 1B (0.75 g). MS (ESI): m / z 501.30, 503.28 (M + H); 523.20, 525.20 (M + Na).

  Step 1C

化合物１Ｂ（０．７５ｇ、１．５ｍｍｏｌ）、ビニルトリフルオロホウ酸カリウム（０．６１ｇ、４．５ｍｍｏｌ）、トリエチルアミン（０．６３ｍｌ、４．５ｍｍｏｌ）およびエタノール（１５ｍｌ）の混合物に、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）クロリド錯体を、ＣＨ_２Ｃｌ_２（５０ｍｇ、０．０６ｍｍｏｌ）とともに添加した。生じた混合物を７５℃で２０時間撹拌し、室温に冷却し、１０％ＫＨＳＯ４水溶液でクエンチし、酢酸エチルで抽出した（３×）。合わせた有機層を脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝１：０から４：１）により精製して、１Ｃ（０．２７ｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ４４９．３２（Ｍ＋Ｈ）、４７１．２９（Ｍ＋Ｎａ）。

To a mixture of compound 1B (0.75 g, 1.5 mmol), potassium vinyltrifluoroborate (0.61 g, 4.5 mmol), triethylamine (0.63 ml, 4.5 mmol) and ethanol (15 ml), 1,1 '-Bis (diphenylphosphino) ferrocenepalladium (II) chloride complex was added along with CH ₂ Cl ₂ (50 mg, 0.06 mmol). The resulting mixture was stirred at 75 ° C. for 20 hours, cooled to room temperature, quenched with 10% aqueous KHSO 4 and extracted with ethyl acetate (3 ×). The combined organic layers were dried (MgSO4), concentrated in vacuo, and the residue was purified by chromatography (hexane / EtOAC = 1: 0 to 4: 1) to yield 1C (0.27 g). MS (ESI): m / z 449.32 (M + H), 471.29 (M + Na).

  Step 1D

化合物１Ｃ（０．６ｍｍｏｌ）のジクロロメタン（２ｍｌ）中溶液を、４Ｍ ＨＣｌ／ジオキサン（３ｍｌ、１２ｍｍｏｌ）で処理した。生じた混合物を室温で１時間撹拌し、真空中で濃縮脱水して、化合物１Ｄ（１００％）のＨＣｌ塩を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ３４９．０９（Ｍ＋Ｈ）。

A solution of compound 1C (0.6 mmol) in dichloromethane (2 ml) was treated with 4M HCl / dioxane (3 ml, 12 mmol). The resulting mixture was stirred at room temperature for 1 hour and concentrated to dryness in vacuo to give the HCl salt of compound 1D (100%). MS (ESI): m / z 349.09 (M + H).

  Step 1E

化合物１Ｄ（ＨＣｌ塩、７７ｍｇ、０．２ｍｍｏｌ）、化合物１Ｅ１（７７ｍｇ、０．３ｍｍｏｌ）およびＤＩＰＥＡ（０．１１ｍｌ、０．６３ｍｍｏｌ）のＤＭＦ（２ｍｌ）中溶液に、０℃で、ＨＡＴＵ（１１５ｍｇ、０．３ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝９：１から６：４）により精製して、化合物１Ｅ（５７ｍｇ）を得た。ＭＳ（ＥＳＩ）：ｍ／ｅ５８８．１３（Ｍ＋Ｈ）。

To a solution of compound 1D (HCl salt, 77 mg, 0.2 mmol), compound 1E1 (77 mg, 0.3 mmol) and DIPEA (0.11 ml, 0.63 mmol) in DMF (2 ml) at 0 ° C., HATU (115 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAC = 9: 1 to 6: 4) to give compound 1E (57 mg). MS (ESI): m / e 588.13 (M + H).

  Step 1F

化合物１Ｅ（５０ｍｇ、０．０９ｍｍｏｌ）のジクロロメタン（１５ｍｌ）中溶液に、Ｈｏｖｅｙｄａ−Ｇｒｕｂｂｓの第一世代または同様の触媒（５ｍｏｌ当量％）を添加した。反応混合物を４０℃で２０時間撹拌した。溶媒を次いで蒸発させ、残留物を、勾配溶出（ヘキサン／ＥｔＯＡＣ＝６：１から３：１）を使用するシリカゲルフラッシュクロマトグラフィーにより精製し、大環状化合物１Ｆ（１０ｍｇ）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ５６０．３８（Ｍ＋Ｈ）。

To a solution of compound 1E (50 mg, 0.09 mmol) in dichloromethane (15 ml) was added Hoveyda-Grubbs first generation or similar catalyst (5 mol eq%). The reaction mixture was stirred at 40 ° C. for 20 hours. The solvent was then evaporated and the residue was purified by silica gel flash chromatography using gradient elution (hexane / EtOAC = 6: 1 to 3: 1) to give Macrocyclic Compound 1F (10 mg). MS (ESI) m / z 560.38 (M + H).

  Step 1G

化合物１Ｆ（１０ｍｇ、０．０１７ｍｍｏｌ）のＴＨＦ／ＭｅＯＨ（２ｍｌ／１ｍｌ）中溶液に、１Ｎ水酸化リチウム（１ｍｌ、１ｍｍｏｌ）を添加した。混合物を室温で２０時間撹拌した。大部分の有機溶媒を真空で蒸発させ、生じた残留物を水で希釈し、ｐＨ５から６に酸性化した。混合物をＥｔＯＡｃで３回抽出した。合わせた有機抽出物を脱水させ（ＭｇＳＯ_４）、濾過し、真空中で濃縮して、１Ｇ（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ５４６．３６（Ｍ＋Ｈ）。

To a solution of compound 1F (10 mg, 0.017 mmol) in THF / MeOH (2 ml / 1 ml) was added 1N lithium hydroxide (1 ml, 1 mmol). The mixture was stirred at room temperature for 20 hours. Most of the organic solvent was evaporated in vacuo and the resulting residue was diluted with water and acidified to pH 5-6. The mixture was extracted 3 times with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 1G (100%). MS (ESI): m / z 546.36 (M + H).

  Step 1H

化合物１Ｈ１（６．６ｇ、２５．８５ｍｍｏｌ）のＴＨＦ（１１５ｍｌ）中溶液に、−７８℃で、ＮａＨＭＤＳ（ＴＨＦ中１．０Ｍ、２８．５ｍｌ、２８．５ｍｍｏｌ）をゆっくり添加した。混合物を−７８℃で１時間撹拌した後、ＴＨＦ（１５ｍｌ）中のＢｏｃ２Ｏ（６．８ｇ、１．２当量）を添加した。生じた混合物を撹拌し、温度を徐々に室温まで終夜上げた。反応混合物をＥｔＯＡｃで希釈し、ブライン（２×）で洗浄し、脱水させ（ＭｇＳＯ４）、真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡｃ＝１：０から８５：１５）により精製して、１Ｈ（８．０５ｇ）を得た。

To a solution of compound 1H1 (6.6 g, 25.85 mmol) in THF (115 ml) at −78 ° C. was slowly added NaHMDS (1.0 M in THF, 28.5 ml, 28.5 mmol). After the mixture was stirred at −78 ° C. for 1 h, Boc 2 O (6.8 g, 1.2 eq) in THF (15 ml) was added. The resulting mixture was stirred and the temperature was gradually raised to room temperature overnight. The reaction mixture was diluted with EtOAc, washed with brine (2x), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAc = 1: 0 to 85:15) to give 1H (8.05 g).

  Step 1I

化合物１Ｈ（０．５ｇ、１．４ｍｍｏｌ）のイソ−プロパノール（５ｍｌ）中溶液に、ＮａＩＯ４（０．９ｇ、４．２ｍｍｏｌ）、続いて水（５ｍｌ）を添加した。この激しく撹拌した混合物に、ＯｓＯ４（０．４％水溶液、０．２２ｍ、２．５当量％）を添加した。生じた混合物を室温で４時間撹拌し、ＥｔＯＡｃで希釈し、ＮａＨＣＯ３水溶液、Ｎａ２Ｓ２Ｏ３水溶液、ブラインで洗浄し、脱水させ（ＭｇＳＯ４）、真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡｃ＝１：０から８５：１５）により精製して、１Ｉ（０．３７ｇ）を得た。

To a solution of compound 1H (0.5 g, 1.4 mmol) in iso-propanol (5 ml) was added NaIO4 (0.9 g, 4.2 mmol) followed by water (5 ml). To this vigorously stirred mixture was added OsO4 (0.4% aqueous solution, 0.22 m, 2.5 equiv%). The resulting mixture was stirred at room temperature for 4 hours, diluted with EtOAc, washed with aqueous NaHCO3, aqueous Na2S2O3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAc = 1: 0 to 85:15) to give 1I (0.37 g).

  Step 1J

化合物１Ｉ（２．９ｇ、８．１ｍｍｏｌ）のジクロロメタン（２５ｍｌ）中溶液に、−７８℃で、三フッ化ジエチルアミノ硫黄（ＤＡＳＴ）（２．７ｍｌ、２０．２５ｍｍｏｌ）を添加した。生じた混合物を−７８℃で１時間撹拌し、次いで温度を徐々に室温に６時間かけて上げ、ＥｔＯＡｃで希釈し、ＮａＨＣＯ３水溶液（２×）、ブラインで洗浄し、脱水させ（ＭｇＳＯ４）、真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡｃ＝１：０から８５：１５）により精製して、１Ｊ（１．４９ｇ）を得た。回収された出発原料１Ｉ（１．２ｇ）。

To a solution of compound 1I (2.9 g, 8.1 mmol) in dichloromethane (25 ml) at −78 ° C. was added diethylaminosulfur trifluoride (DAST) (2.7 ml, 20.25 mmol). The resulting mixture was stirred at −78 ° C. for 1 hour, then the temperature was gradually raised to room temperature over 6 hours, diluted with EtOAc, washed with aqueous NaHCO 3 (2 ×), brine, dried (MgSO 4), vacuum Concentrated with. The residue was purified by silica gel chromatography (hexane / EtOAc = 1: 0 to 85:15) to give 1J (1.49 g). Recovered starting material 1I (1.2 g).

  Step 1K

化合物１Ｊ（３８１ｍｇ、１．４ｍｍｏｌ）のＴＨＦ／ＭｅＯＨ（２４ｍｌ−１２ｍｌ）中溶液に、水酸化リチウム水和溶液（１．０Ｍ、１２ｍｌ、１２ｍｍｏｌ）を添加した。混合物を室温で２日間撹拌した。大部分の有機溶媒を真空で蒸発させ、生じた残留物を水で希釈し、ｐＨ５から６に酸性化した。混合物をＥｔＯＡｃで３回抽出した。合わせた有機抽出物を脱水させ（ＭｇＳＯ_４）、濾過し、真空中で濃縮して、化合物１Ｋ（およそ１００％）が得られ、次のステップで直接使用した。

To a solution of compound 1J (381 mg, 1.4 mmol) in THF / MeOH (24 ml-12 ml) was added lithium hydroxide hydrate solution (1.0 M, 12 ml, 12 mmol). The mixture was stirred at room temperature for 2 days. Most of the organic solvent was evaporated in vacuo and the resulting residue was diluted with water and acidified to pH 5-6. The mixture was extracted 3 times with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give compound 1K (approximately 100%), which was used directly in the next step.

  Step 1L

化合物１Ｋ（１．３３ｍｍｏｌ）およびカルボニルジイミダゾール（３２３ｍｇ、２．ｍｍｏｌ）を無水ＤＭＦ ５ｍｌ中に溶解し、生じた溶液を４０℃で１時間撹拌した。シクロプロピルスルホンアミド（４８３ｍｇ、４ｍｍｏｌ）を反応混合物に添加し、続いてＤＢＵ（０．２６ｍｌ、１．７ｍｍｏｌ）を添加した。反応混合物を４０℃で１８時間撹拌した。反応混合物を酢酸エチルで希釈し、半飽和ＮａＣｌ水溶液で４回洗浄した。有機層を無水（ＭｇＳＯ４）上で脱水させ、真空中で濃縮して、化合物１Ｌを生成し、これを次のステップ１Ｍで直接使用した。

Compound 1K (1.33 mmol) and carbonyldiimidazole (323 mg, 2. mmol) were dissolved in 5 ml of anhydrous DMF and the resulting solution was stirred at 40 ° C. for 1 hour. Cyclopropylsulfonamide (483 mg, 4 mmol) was added to the reaction mixture followed by DBU (0.26 ml, 1.7 mmol). The reaction mixture was stirred at 40 ° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed 4 times with half-saturated aqueous NaCl. The organic layer was dried over anhydrous (MgSO4) and concentrated in vacuo to yield compound 1L, which was used directly in the next step 1M.

  Alternatively, compound 1L was made from compound 1K using the coupling reagent EDCI / DMAP and cyclopropylsulfonamide.

  Step 1M

上記化合物１Ｌのジクロロメタン（１ｍｌ）中溶液を、１，４−ジオキサン（４ｍｌ、１６ｍｍｏｌ）中の４Ｎ ＨＣｌで処理した。混合物を室温で１時間撹拌し、濃縮乾固させて、１Ｍが得られ、次のステップで直接使用した。

A solution of the above compound 1L in dichloromethane (1 ml) was treated with 4N HCl in 1,4-dioxane (4 ml, 16 mmol). The mixture was stirred at room temperature for 1 hour and concentrated to dryness to give 1M, which was used directly in the next step.

  Step 1N

化合物１Ｇ（０．０１ｍｍｏｌ）、１Ｍ（１当量）およびＤＩＰＥＡ（０．０５ｍｌ、０．２８７ｍｍｏｌ）のＤＭＦ（１ｍｌ）中溶液に、０℃で、ＨＡＴＵ（２４ｍｇ、０．０６３ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物を分取用ＨＰＬＣにより精製して、標題化合物（１ｍｇ）を得た。ＭＳ（ＥＳＩ）；ｍ／ｚ７８２．２７（Ｍ＋Ｈ）。

To a solution of compound 1G (0.01 mmol), 1M (1 eq) and DIPEA (0.05 ml, 0.287 mmol) in DMF (1 ml) at 0 ° C. was added HATU (24 mg, 0.063 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (1 mg). MS (ESI); m / z 784.27 (M + H).

Example 2
A compound of formula XI wherein:

］

]

を、実施例１に記載されているのと同じ手順を使用して調製した。ＭＳ（ＥＳＩ）：ｍ／ｚ７８２．２７（Ｍ＋Ｈ）。

Was prepared using the same procedure as described in Example 1. MS (ESI): m / z 784.27 (M + H).

Example 3
A compound of formula XI wherein:

］

]

  Step 3A

化合物３Ａ１（８０％、３．０５ｇ、１２，３ｍｍｏｌ）、臭化アリル（２ｍｌ、２３ｍｍｏｌ）のＤＭＦ（２０ｍｌ）中溶液に、炭酸セシウム（７．６ｇ、２３．３ｍｍｏｌ）を添加した。生じた混合物を４０℃で２２時間撹拌し、室温に冷却し、ＥｔＯＡｃで希釈し、水、ブライン（３×）で洗浄し、脱水させ（ＭｇＳＯ４）、濃縮し、結晶化して、化合物３Ａ（２．２５ｇ）を生成した。

To a solution of compound 3A1 (80%, 3.05 g, 12,3 mmol), allyl bromide (2 ml, 23 mmol) in DMF (20 ml) was added cesium carbonate (7.6 g, 23.3 mmol). The resulting mixture was stirred at 40 ° C. for 22 hours, cooled to room temperature, diluted with EtOAc, washed with water, brine (3 ×), dried (MgSO 4), concentrated and crystallized to give compound 3A (2 .25 g).

  Step 3B

化合物３Ａ（２．２５ｇ、９．５ｍｍｏｌ）、ヒドロキシアミン塩酸塩（１．９５ｇ、２８ｍｍｏｌ）およびメタノール（５０ｍ）の混合物を、還流下で５時間加熱し、室温に冷却し、ＥｔＯＡｃで希釈し、ＮａＨＣＯ３水溶液、ブラインで洗浄し、脱水させ（ＭｇＳＯ４）、濃縮乾固させて、化合物３Ｂ（２．２ｇ）を得た。

A mixture of compound 3A (2.25 g, 9.5 mmol), hydroxyamine hydrochloride (1.95 g, 28 mmol) and methanol (50 m) was heated under reflux for 5 hours, cooled to room temperature, diluted with EtOAc, Washed with aqueous NaHCO3, brine, dried (MgSO4) and concentrated to dryness to give compound 3B (2.2 g).

  Step 3C

化合物３Ｃ（２．１７ｇ、８．６４ｍｍｏｌ）、化合物３Ｃ１（９．６ｍｍｏｌ）のＤＭＦ（１４ｍｌ）中溶液に、炭酸セシウム（４．７ｇ、１４．４ｍｍｏｌ）を添加した。生じた混合物を５０℃で２２時間撹拌し、室温に冷却し、ＥｔＯＡｃで希釈し、水、ブライン（３×）で洗浄し、脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝１：０から４：１）により精製して、３Ｃ（２．０９ｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ４７９．２９（Ｍ＋Ｈ）。

To a solution of compound 3C (2.17 g, 8.64 mmol), compound 3C1 (9.6 mmol) in DMF (14 ml) was added cesium carbonate (4.7 g, 14.4 mmol). The resulting mixture was stirred at 50 ° C. for 22 hours, cooled to room temperature, diluted with EtOAc, washed with water, brine (3 ×), dried (MgSO 4) and concentrated in vacuo, and the residue was chromatographed. Purification by (hexane / EtOAC = 1: 0 to 4: 1) yielded 3C (2.09 g). MS (ESI): m / z 479.29 (M + H).

  Step 3D

化合物３Ｃ（４．４ｍｍｏｌ）のジクロロメタン（５ｍｌ）中溶液を、４Ｍ ＨＣｌ／ジオキサン（８ｍｌ、３２ｍｍｏｌ）で処理した。生じた混合物を室温で１時間撹拌し、真空中で濃縮乾固して、化合物３ＤのＨＣｌ塩（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ３７９．２２（Ｍ＋Ｈ）。

A solution of compound 3C (4.4 mmol) in dichloromethane (5 ml) was treated with 4M HCl / dioxane (8 ml, 32 mmol). The resulting mixture was stirred at room temperature for 1 hour and concentrated to dryness in vacuo to give the HCl salt of compound 3D (100%). MS (ESI): m / z 379.22 (M + H).

  Step 3E

化合物３Ｄ（４．４ｍｍｏｌ）、Ｂｏｃ−Ｌ−ｔｅｒｔ−ロイシン（１．２２ｇ、５．２８ｍｍｏｌ）およびＤＩＰＥＡ（２．５ｍｌ、１３．２ｍｍｏｌ）のＤＭＦ（１５ｍｌ）中溶液に、０℃で、ＨＡＴＵ（２．０ｇ、５．２６ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝６：１から４：１）により精製して、化合物３Ｅ（１．６ｇ）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ５９２．３９（Ｍ＋Ｈ）、６１４．３７（Ｍ＋Ｎａ）。

To a solution of compound 3D (4.4 mmol), Boc-L-tert-leucine (1.22 g, 5.28 mmol) and DIPEA (2.5 ml, 13.2 mmol) in DMF (15 ml) at 0 ° C. at HATU ( 2.0 g, 5.26 mmol) was added. The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAC = 6: 1 to 4: 1) to give compound 3E (1.6 g). MS (ESI): m / z 592.39 (M + H), 614.37 (M + Na).

  Step 3F

化合物３Ｅ（２．７ｍｍｏｌ）のジクロロメタン（５ｍｌ）中溶液を、４Ｍ ＨＣｌ／ジオキサン（８ｍｌ、４０ｍｍｏｌ）で処理した。生じた混合物を室温で１時間撹拌し、真空中で濃縮乾固して、化合物３ＦのＨＣｌ塩（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ４９２．２７（Ｍ＋Ｈ）。

A solution of compound 3E (2.7 mmol) in dichloromethane (5 ml) was treated with 4M HCl / dioxane (8 ml, 40 mmol). The resulting mixture was stirred at room temperature for 1 hour and concentrated to dryness in vacuo to give the HCl salt of compound 3F (100%). MS (ESI): m / z 492.27 (M + H).

  Step 3G

化合物３Ｆ（０．５ｇ、０．９４７ｍｍｏｌ）をジクロロメタン（１０ｍ）中に溶解し、０℃に冷却し、トリエチルアミン（０．５３ｍｌ、４当量）、続いてクロロホルメート化合物３Ｇ１（０．２ｍｌ、２当量）で処理した。混合物を室温で０．５時間から１時間撹拌し、酢酸エチルで希釈し、半飽和ＮａＣｌ溶液で２回洗浄し、脱水させ（ＭｇＳＯ４）、真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡｃ＝９：１から７：３）により精製して、化合物３Ｇ（４７０ｍｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ５７６．２１（Ｍ＋Ｈ）。

Compound 3F (0.5 g, 0.947 mmol) was dissolved in dichloromethane (10 m), cooled to 0 ° C., triethylamine (0.53 ml, 4 eq) followed by chloroformate compound 3G1 (0.2 ml, 2 ml). Equivalent). The mixture was stirred at room temperature for 0.5 to 1 hour, diluted with ethyl acetate, washed twice with half-saturated NaCl solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAc = 9: 1 to 7: 3) to yield compound 3G (470 mg). MS (ESI): m / z 576.21 (M + H).

  Step 3H

化合物３Ｇ（４５０ｍｇ、０．７８ｍｍｏｌ）のジクロロメタン（１００ｍｌ）中溶液に、Ｈｏｖｅｙｄａ−Ｇｒｕｂｂｓの第一世代または同様の触媒（５ｍｏｌ当量％）を添加した。反応混合物を４０℃で２０時間撹拌した。溶媒を次いで蒸発させ、残留物を、勾配溶出（ヘキサン／ＥｔＯＡＣ＝９：１から６：４）を使用するシリカゲルフラッシュクロマトグラフィーにより精製して、大環状化合物３Ｈ（２６３ｍｇ）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ５４８．１１（Ｍ＋Ｈ）。

To a solution of compound 3G (450 mg, 0.78 mmol) in dichloromethane (100 ml) was added Hoveyda-Grubbs first generation or similar catalyst (5 mol eq%). The reaction mixture was stirred at 40 ° C. for 20 hours. The solvent was then evaporated and the residue was purified by silica gel flash chromatography using gradient elution (hexane / EtOAC = 9: 1 to 6: 4) to give Macrocyclic Compound 3H (263 mg). MS (ESI) m / z 548.11 (M + H).

  Step 3I

化合物３Ｈ（８５ｍｇ、０．１５５ｍｍｏｌ）のＴＨＦ／ＭｅＯＨ（１０ｍｌ／５ｍｌ）中溶液に、１Ｎ水酸化リチウム（５ｍｌ、５ｍｍｏｌ）を添加した。混合物を室温で２０時間撹拌した。大部分の有機溶媒を真空で蒸発させ、生じた残留物を水で希釈し、ｐＨ５から６に酸性化した。混合物をＥｔＯＡｃで３回抽出した。合わせた有機抽出物を脱水させ（ＭｇＳＯ_４）、濾過し、真空中で濃縮して、３Ｉ（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ５３４．１２（Ｍ＋Ｈ）。

To a solution of compound 3H (85 mg, 0.155 mmol) in THF / MeOH (10 ml / 5 ml) was added 1N lithium hydroxide (5 ml, 5 mmol). The mixture was stirred at room temperature for 20 hours. Most of the organic solvent was evaporated in vacuo and the resulting residue was diluted with water and acidified to pH 5-6. The mixture was extracted 3 times with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 3I (100%). MS (ESI): m / z 534.12 (M + H).

  Step 3J

化合物１Ｇ（０．０５７ｍｍｏｌ）、１Ｍ（１当量）およびＤＩＰＥＡ（０．１ｍｌ、０．５７５ｍｍｏｌ）のＤＭＦ（４ｍｌ）中溶液に、０℃で、ＨＡＴＵ（４４ｍｇ、０．１１５ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物を分取用ＨＰＬＣにより精製して、標題化合物（２ｍｇ）を得た。ＭＳ（ＥＳＩ）；ｍ／ｚ７７０．２１（Ｍ＋Ｈ）。

To a solution of compound 1G (0.057 mmol), 1M (1 eq) and DIPEA (0.1 ml, 0.575 mmol) in DMF (4 ml) at 0 ° C. was added HATU (44 mg, 0.115 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (2 mg). MS (ESI); m / z 770.21 (M + H).

Example 4
A compound of formula XI wherein:

］

]

を実施例３に記載されているのと同じ手順を使用して調製した。ＭＳ（ＥＳＩ）：ｍ／ｚ７７０．２０（Ｍ＋Ｈ）。

Was prepared using the same procedure as described in Example 3. MS (ESI): m / z 770.20 (M + H).

Example 5
A compound of formula XI wherein:

］

]

を実施例３に記載されているのと同じ手順を使用して調製した。ＭＳ（ＥＳＩ）：ｍ／ｚ７７０．２１（Ｍ＋Ｈ）。

Was prepared using the same procedure as described in Example 3. MS (ESI): m / z 770.21 (M + H).

Example 6
A compound of formula XI wherein:

］

]

を実施例３に記載されているのと同じ手順を使用して調製した。ＭＳ（ＥＳＩ）：ｍ／ｚ７７０．２０（Ｍ＋Ｈ）。

Was prepared using the same procedure as described in Example 3. MS (ESI): m / z 770.20 (M + H).

  Examples 7 to 140, compounds of formula XI in Table 1 are made according to the procedures described in Examples 1 to 6 and the Synthetic Methods section.

Example 141
A compound of formula XII [wherein

］。

].

  Step 141A

１−ブロモ−３−ヨードベンゼン（３．８ｍｌ、３０ｍｍｏｌ）、フェニルアセチレン（１．６５ｍｌ、１５ｍｍｏｌ）、ヨウ化銅（２８５ｍｇ、１．５ｍｍｏｌ）、ＴＨＦ（２０ｍｌ）およびＴＭＥＤＡ（２０ｍ）の混合物に、テトラキス（トリフェニルホスフィン）パラジウム（０）（６２０ｍｇ、０．５４ｍｍｏｌ）を添加した。生じた混合物を５０℃で２０時間撹拌し、室温に冷却し、ＥｔＯＡｃ（２５０ｍｌ）で希釈し、ＮａＨＣＯ３水溶液、ブラインで洗浄し、脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン）により精製して、１４１ａ（２．７ｇ）を生成した。

To a mixture of 1-bromo-3-iodobenzene (3.8 ml, 30 mmol), phenylacetylene (1.65 ml, 15 mmol), copper iodide (285 mg, 1.5 mmol), THF (20 ml) and TMEDA (20 m), Tetrakis (triphenylphosphine) palladium (0) (620 mg, 0.54 mmol) was added. The resulting mixture was stirred at 50 ° C. for 20 hours, cooled to room temperature, diluted with EtOAc (250 ml), washed with aqueous NaHCO 3, brine, dried (MgSO 4) and concentrated in vacuo and the residue chromatographed. Purification by (hexane) yielded 141a (2.7 g).

  Step 141B

化合物１４１ａ（０．５ｇ、１．９４ｍｍｏｌ）、トリメチルシリルアジ化物（０．９ｍｌ、６．８ｍｍｏｌ）およびＤＭＦ（３ｍｌ）の混合物を、１３５℃で３６時間撹拌し、室温に冷却し、ＥｔＯＡｃで希釈し、ブライン（３×）で洗浄し、脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン／ＡｃＯＥｔ＝４：１から３：１）により精製して、１４１ｂ（３５０ｍｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ３００．０６、３０２．０３（Ｍ＋Ｈ）。

A mixture of compound 141a (0.5 g, 1.94 mmol), trimethylsilyl azide (0.9 ml, 6.8 mmol) and DMF (3 ml) was stirred at 135 ° C. for 36 hours, cooled to room temperature and diluted with EtOAc. , Washed with brine (3 ×), dried (MgSO 4), concentrated in vacuo, and the residue was purified by chromatography (hexane / AcOEt = 4: 1 to 3: 1) to give 141b (350 mg). Generated. MS (ESI): m / z 300.06, 302.03 (M + H).

  Step 141C

化合物１４１ｂ（３３９ｍｇｇ、１．１３ｍｍｏｌ）、化合物１４１ｃ−１（４０１ｍｇ、１．２４ｍｍｏｌ）、炭酸セシウム（７３６ｍｇ、２．２６ｍｍｏｌ）およびＤＭＦ（５ｍｌ）の混合物を、７０℃で２０時間撹拌し、ＥｔＯＡｃで希釈し、ブライン（３×）で洗浄し、脱水させ（ＭｇＳＯ４）、真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡｃ＝９：１から８：２）により精製して、１４１ｃ（３７３ｍｇ）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ５２７．２０、５２９．２０（Ｍ＋Ｈ）。

A mixture of compound 141b (339 mgg, 1.13 mmol), compound 141c-1 (401 mg, 1.24 mmol), cesium carbonate (736 mg, 2.26 mmol) and DMF (5 ml) was stirred at 70 ° C. for 20 h and EtOAc. Diluted, washed with brine (3x), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAc = 9: 1 to 8: 2) to give 141c (373 mg). MS (ESI): m / z 527.20, 529.20 (M + H).

  Step 141D

化合物１４１ｃ（３６５ｍｇｇ、０．６９ｍｍｏｌ）、ビニルトリフルオロホウ酸カリウム（２８０ｍｇ、２．１ｍｍｏｌ）、トリエチルアミン（０．３ｍｌ）およびエタノール（８ｍｌ）の混合物に、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）クロリド錯体をＣＨ_２Ｃｌ_２（５０ｍｇ、０．０５５ｍｍｏｌ）とともに添加した。生じた混合物を７５℃で１５時間撹拌し、室温に冷却し、１０％ＫＨＳＯ４水溶液でクエンチし、酢酸エチルで抽出した（３×）。合わせた有機層を脱水させ（ＭｇＳＯ４）、真空下で濃縮し、残留物をクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝１：０から４：１）により精製して、１４１ｄ（２２６ｇ）を生成した。ＭＳ（ＥＳＩ）：ｍ／ｚ４７５．１４（Ｍ＋Ｈ）、５１３．０８（Ｍ＋Ｋ）。

To a mixture of compound 141c (365 mgg, 0.69 mmol), potassium vinyltrifluoroborate (280 mg, 2.1 mmol), triethylamine (0.3 ml) and ethanol (8 ml), 1,1′-bis (diphenylphosphino) Ferrocene palladium (II) chloride complex was added along with CH ₂ Cl ₂ (50 mg, 0.055 mmol). The resulting mixture was stirred at 75 ° C. for 15 hours, cooled to room temperature, quenched with 10% aqueous KHSO 4 and extracted with ethyl acetate (3 ×). The combined organic layers were dried (MgSO4), concentrated in vacuo, and the residue was purified by chromatography (hexane / EtOAC = 1: 0 to 4: 1) to yield 141d (226 g). MS (ESI): m / z 475.14 (M + H), 513.08 (M + K).

  Step 141E

化合物１４１ｄ（２２０ｍｇ、０．４７ｍｍｏｌ）のジクロロメタン（１ｍｌ）中溶液を、４Ｍ ＨＣｌ／ジオキサン（３ｍｌ、１２ｍｍｏｌ）で処理した。生じた混合物を室温で１時間撹拌し、真空中で濃縮乾固して、化合物１４１ｅのＨＣｌ塩（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｅ３７５．０７（Ｍ＋Ｈ）。

A solution of compound 141d (220 mg, 0.47 mmol) in dichloromethane (1 ml) was treated with 4M HCl / dioxane (3 ml, 12 mmol). The resulting mixture was stirred at room temperature for 1 hour and concentrated to dryness in vacuo to give the HCl salt of compound 141e (100%). MS (ESI): m / e 375.07 (M + H).

  Step 141F

化合物１４１ｅ（ＨＣｌ塩、０．２３ｍｍｏｌ）、化合物１４１ｆ１（９０ｍｇ、０．３５ｍｍｏｌ）およびＤＩＰＥＡ（０．１６ｍｌ、０．９２ｍｍｏｌ）のＤＭＦ（３ｍｌ）中溶液に、０℃で、ＨＡＴＵ（１４０ｍｇ、０．３７ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／ＥｔＯＡＣ＝９：１から７：３）により精製して、化合物１４１ｆ（１３０ｍｇ）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ６１４．２４（Ｍ＋Ｈ）。

To a solution of compound 141e (HCl salt, 0.23 mmol), compound 141f1 (90 mg, 0.35 mmol) and DIPEA (0.16 ml, 0.92 mmol) in DMF (3 ml) at 0 ° C., HATU (140 mg, 0. 37 mmol) was added. The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography (hexane / EtOAC = 9: 1 to 7: 3) to give compound 141f (130 mg). MS (ESI): m / z 614.24 (M + H).

  Step 141G

化合物１４１ｆ（４７ｍｇ、０．１９ｍｍｏｌ）のジクロロメタン（２０ｍｌ）中溶液に、Ｈｏｖｅｙｄａ−Ｇｒｕｂｂｓの第一世代触媒（５ｍｏｌ当量％）を添加した。反応混合物を４０℃で２０時間撹拌した。溶媒を次いで蒸発させ、残留物を、勾配溶出（ヘキサン／ＥｔＯＡＣ＝９：１から７：３）を使用するシリカゲルフラッシュクロマトグラフィーにより精製して、大環状化合物１４１ｇ（２５ｍｇ）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ５８６．２７（Ｍ＋Ｈ）。

To a solution of compound 141f (47 mg, 0.19 mmol) in dichloromethane (20 ml) was added Hoveyda-Grubbs first generation catalyst (5 mol eq%). The reaction mixture was stirred at 40 ° C. for 20 hours. The solvent was then evaporated and the residue was purified by silica gel flash chromatography using gradient elution (hexane / EtOAC = 9: 1 to 7: 3) to give 141 g (25 mg) of macrocyclic compound. MS (ESI) m / z 586.27 (M + H).

  Step 141H

化合物１４１ｇ（２０ｍｇ、０．０３４ｍｍｏｌ）のＴＨＦ／ＭｅＯＨ（４ｍｌ／２ｍｌ）中溶液に、１Ｎ水酸化リチウム（２ｍｌ、２ｍｍｏｌ）を添加した。混合物を室温で２０時間撹拌した。大部分の有機溶媒を真空で蒸発させ、生じた残留物を水で希釈し、ｐＨ５から６に酸性化した。混合物をＥｔＯＡｃで３回抽出した。合わせた有機抽出物を脱水させ（ＭｇＳＯ_４）、濾過し、真空中で濃縮して、１４１ｈ（１００％）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ５７２．２８（Ｍ＋Ｈ）。

To a solution of compound 141g (20 mg, 0.034 mmol) in THF / MeOH (4 ml / 2 ml) was added 1N lithium hydroxide (2 ml, 2 mmol). The mixture was stirred at room temperature for 20 hours. Most of the organic solvent was evaporated in vacuo and the resulting residue was diluted with water and acidified to pH 5-6. The mixture was extracted 3 times with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 141h (100%). MS (ESI): m / z 572.28 (M + H).

  Step 141I

標題化合物を、実施例１ステップ１Ｎに記載されているのと同じ手順を使用して、１４１ｈから調製した。ＭＳ（ＥＳＩ）：ｍ／ｚ８０８．５５（Ｍ＋Ｈ）。

The title compound was prepared from 141h using the same procedure as described in Example 1, Step 1N. MS (ESI): m / z 808.55 (M + H).

  Examples 142 to 206, compounds of formula XII in Table 2 are made according to the procedures described in Examples 1 to 141 and the Synthetic Methods section.

Example 207
A compound of formula XIII, wherein

］

]

化合物２０７−１（１６ｍｇ、０．０３ｍｍｏｌ）、１Ｍ（１当量）およびＤＩＰＥＡ（０．０６ｍｌ、０．３４４ｍｍｏｌ）のＤＭＦ（１ｍｌ）中溶液に、０℃で、ＨＡＴＵ（２０ｍｇ、０．０５２ｍｍｏｌ）を添加した。混合物を室温で１８時間撹拌し、ＥｔＯＡｃで希釈し、半飽和ＮａＣｌ溶液で４回洗浄した。有機相を無水ＭｇＳＯ_４上で脱水させ、濾過し、次いで真空で濃縮した。残留物を分取用ＨＰＬＣにより精製して、標題化合物（１１ｍｇ）を得た。ＭＳ（ＥＳＩ）；ｍ／ｚ７６３．２６（Ｍ＋Ｈ）。

To a solution of compound 207-1 (16 mg, 0.03 mmol), 1M (1 eq) and DIPEA (0.06 ml, 0.344 mmol) in DMF (1 ml) at 0 ° C. was added HATU (20 mg, 0.052 mmol). Added. The mixture was stirred at room temperature for 18 hours, diluted with EtOAc and washed 4 times with half-saturated NaCl solution. The organic phase was dried over anhydrous MgSO ₄ , filtered and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg). MS (ESI); m / z 763.26 (M + H).

Example 208
A compound of formula XIII [wherein

］

]

実施例２０７の化合物（４ｍｇ、０．００５ｍｍｏｌ）、Ｐｄ−Ｃ（１０％、４ｍｇ）および酢酸エチル（４ｍｌ）の混合物を大気圧下で０．５時間水素化し、濾過し、酢酸エチルで洗浄した。濾過を濃縮し、残留物を分取用ＨＰＬＣにより精製して、標題化合物（２ｍｇ）を得た。ＭＳ（ＥＳＩ）：ｍ／ｚ７６５．３２（Ｍ＋Ｈ）。

A mixture of the compound of Example 207 (4 mg, 0.005 mmol), Pd-C (10%, 4 mg) and ethyl acetate (4 ml) was hydrogenated at atmospheric pressure for 0.5 h, filtered and washed with ethyl acetate. . The filtration was concentrated and the residue was purified by preparative HPLC to give the title compound (2 mg). MS (ESI): m / z 765.32 (M + H).

  The compounds of Formula XIII in Examples 209 to 272, Table 3, are made according to the procedures described in Examples 1 to 208 and the Synthetic Methods section.

  Examples 273 to 338, compounds of formula XIV in Table 4, are made according to the procedures described in Examples 1 to 272 and the Synthetic Methods section.

  The compounds of the present invention exhibit potent inhibitory properties against HCV NS3 protease, and HCV replication (cell-based assay) in replicons containing Huh-7 cell lines. The following examples illustrate assays that can test the anti-HCV effects of compounds of the present invention.

Example 339
NS3 / NS4a Protease Enzyme Assay The activity and inhibition of HCV protease is assayed using an internally quenched fluorogenic substrate. A DABCYL group and an EDANS group are attached to the opposite ends of the short peptide. Quenching of EDANS fluorescence by the DABCYL group is mitigated by proteolytic cleavage. Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.

The assay is performed in full length NS3 HCV protease 1b tethered with NS4A cofactor (final enzyme concentration 1 to 15 nM) in Corning white half area 96 well plates (VWR29444-312 [Corning3693]). The assay buffer is supplemented with 10 μM NS4A cofactor Pep4A (Anaspec 25336 or homemade, MW 1424.8). RET S1 (Ac-Asp-Glu-Asp (EDANS) -Glu-Glu-Abu- [COO] Ala-Ser-Lys- (DABCYL) -NH ₂ , Anaspec 22991, MW 1548.6) as a fluorogenic peptide substrate use. The assay buffer contains 50 mM Hepes, 30 mM NaCl and 10 mM BME at pH 7.5. The enzyme reaction is followed in the absence and presence of inhibitor at room temperature over a 30 minute time course.

  Peptide inhibitors HCV Inh1 (Anaspec 25345, MW796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [−20 ° C.] and HCV Inh2 (Anaspec 25346, MW913.1) Ac-Asp -Glu-Dif-Cha-Cys-OH is used as a control compound.

  IC50 values are calculated using the XL fit of ActivityBase (IDBS) using equation 205: y = A + ((BA) / (l + ((C / x) ^ D))).

Example 340
Cell-based replicon assay Quantification of HCV replicon RNA (HCV cell-based assay) is accomplished using the Huh11-7 cell line (Lohmann et al., Science 285: 110-113, 1999). Cells are seeded in 96-well plates at 4 × 10 ³ cells / well and given a medium containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and nonessential amino acids. Cells are incubated at 37 ° C. in a 7.5% CO ₂ incubator. At the end of the incubation period, Ambion RNAqueous 96 Kit (Catalog No. AM1812) is used to extract and purify total RNA from the cells. In order to amplify HCV RNA so that sufficient material can be detected by HCV specific probes (below), primers specific to HCV (below) are TaqMan One-Step RT-PCR Master Mix Kit (Applied Bio). It mediates both reverse transcription of HCV RNA and amplification of cDNA by polymerase chain reaction (PCR) using Systems Catalog No. 4309169). The nucleotide sequence of the RT-PCR primer located in the NS5B region of the HCV genome is as follows.
HCV forward primer "RBNS5bfor"
5′GCTGCGGCCCGTCGAGCT (SEQ ID NO: 1): HCV reverse primer “RBNS5Brev”
5′CAAGGTCGTCTCCGCATAC (SEQ ID NO: 2).

  Detection of RT-PCR products is performed by Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS), which detects fluorescence emitted when probes labeled with fluorescent reporter dyes and quencher dyes are degraded during the PCR reaction. To achieve using. The increase in the amount of fluorescence is measured during each cycle of PCR and reflects the amount of increase in RT-PCR product. In particular, quantification is based on a threshold cycle where the amplification plot exceeds a defined fluorescence threshold. By comparing the sample threshold cycle to a known standard, the high sensitivity of the relative template concentration in different samples (ABI User Bulletin # 2, December 11, 1997) is measured. The data is analyzed using ABI SDS program version 1.7. The relative template concentration can be converted to RNA copy number by using a standard curve of HCV RNA standard with a known copy number (ABI User Bulletin # 2, December 11, 1997).

RT-PCR product was detected using the following labeled probe.
5 'FAM-CGAAGCTCCAGGAACTGCACGATGCT-TAMRA (SEQ ID NO: 3)
FAM = fluorescent reporter dye.
TAMRA: = quenching dye.

  The RT reaction is performed at 48 ° C. for 30 minutes, followed by PCR. The thermal cycling parameters used for the PCR reaction in the ABI Prism 7500 Sequence Detection System are: one cycle at 95 ° C. for 10 minutes, followed by a first incubation at 95 ° C. for 15 seconds and 1 at 60 ° C. 40 cycles including a second incubation for minutes.

  To normalize the data to an internal control molecule in cellular RNA, RT-PCR is performed with cellular messenger RNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The copy number of GAPDH is very stable in the cell line used. GAPDH RT-PCR was performed on the same RNA sample from which the HCV copy number was determined. GAPDH primers and probes are contained in ABI Pre-Developed TaqMan Assay Kit (Catalog No. 4310884E). The HCV / GAPDH RNA ratio is used to calculate the activity of a compound evaluated for inhibition of HCV RNA replication.

Compound activity as an inhibitor of HCV replication (cell-based assay) in replicons containing Huh-7 cell lines The effect of specific antiviral compounds on HCV replicon RNA levels in Huh-11-7 cells Determined by comparing the amount of HCV RNA normalized to GAPDH (eg, HCV / GAPDH ratio) in DMSO vehicle (negative control) exposed cells. Specifically, the cells are seeded at 4 × 10 ³ cells / well in a 96-well plate, 1) a medium containing 1% DMSO (0% inhibition control), or 2) a medium containing a predetermined concentration of the compound. Incubate with either 1% DMSO. The 96 well plate as described above is then incubated for 4 days at 37 ° C. (EC50 determination). Percent inhibition is defined as follows:
% Inhibition = 100-100 * S / Cl
Where S = HCV RNA copy number / GAPDH RNA copy number ratio in the sample,
HCV RNA copy number / GAPDH RNA copy number ratio in Cl = 0% inhibition control (medium / 1% DMSO).

  A dose response curve of the inhibitor was generated by sequentially adding compounds in wells starting at a maximum concentration of 1.5 uM and ending with a minimum concentration of 0.23 nM at a 3-fold dilution over 3 logs. To do. If the location of the EC50 value is not clearly shown on the curve, a further dilution series (eg 500 nM to 0.08 nM) is performed. The EC50 is determined with the IDBS Activity Base program “XL Fit” using a four parameter non-linear regression fit (model 4.2.1 version # 205, type 16).

  While the invention has been particularly shown and described by reference to this preferred embodiment, various changes in form and detail may be made without departing from the scope of the invention as encompassed by the appended claims. Those skilled in the art will understand what can be done in the art.

Claims (10)

Formula I

Or a pharmaceutically acceptable salt thereof, wherein :
R is
(I) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- , each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N C _{8 alkynyl;} -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 4 _{-C 12} alkylcycloalkyl, or substituted _-C 4 _{-C 12 alkylcycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12 cycloalkenyl;} -C 4 _{-C 12} alkyl cycloalkenyl or substituted _-C 4 _{-C 12} alkyl cycloalkenyl,
(Ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Iii) heterocycloalkyl or substituted heterocycloalkyl,
(Iv) hydrogen; selected from the group consisting of deuterium;
A is absent or selected from — (C═O) —, —S (O) ₂ , —C═N—OR ₁ or —C (═N—CN), wherein R ₁ is
(V) hydrogen,
(Vi) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Vii) heterocycloalkyl or substituted heterocycloalkyl,
(Viii) each O, S or _-C 1 -C ₈ alkyl containing 0, 1, 2 or 3 heteroatoms selected from N,, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C ₂ each containing 0, 1, 2 or 3 heteroatoms, each selected from O, S or N It is selected from -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} group consisting of _{cycloalkenyl,;} -C _{8 alkynyl;} -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12} cycloalkyl
L ₂₀₁ is absent or —C ₁ -C ₁₂ alkylene, —C ₂ -C ₁₂ alkenylene or —C, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N _2- C ₁₂ alkynylene; substituted -C ₁ -C ₁₂ alkylene, substituted -C ₂ -C ₁₂ alkenylene or substituted, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N -C ₂ -C ₁₂ alkynylene; each O, _-C 3 _{-C 12} cycloalkylene or substituted _-C 3 _{-C 12} cycloalkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N An alkylene; —C ₃ -C ₁₂ cycloa each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N Selected from lukenylene or substituted -C ₃ -C ₁₂ cycloalkenylene,
M is absent or selected from O, S, SO, SO ₂ or NR ₁ (R ₁ is as previously defined);
L ₁₀₁ is absent or —C ₁ -C ₁₂ alkylene, —C ₂ -C ₁₂ alkenylene or —C, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N _2- C ₁₂ alkynylene; substituted -C ₁ -C ₁₂ alkylene, substituted -C ₂ -C ₁₂ alkenylene or substituted, each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N -C ₂ -C ₁₂ alkynylene; each O, _-C 3 _{-C 12} cycloalkylene or substituted _-C 3 _{-C 12} cycloalkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N An alkylene; —C ₃ -C ₁₂ cycloa each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N Selected from lukenylene or substituted -C ₃ -C ₁₂ cycloalkenylene,
Z ₁₀₁ is absent, or M, arylene, substituted arylene, selected from heteroarylene alkylene or substituted heteroarylene Ren,
G is selected from —OH, —NH (SO ₂ ) R ₂ , —NH (SO ₂ ) NR ₃ R ₄ and NR ₃ R ₄ ;
R ₂ is
(I) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Ii) heterocycloalkyl; substituted heterocycloalkyl;
(Iii) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl, substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- containing 0, 1, 2 or 3 heteroatoms, each selected from O, S or N C _{8 alkynyl;} selected from substituted heterocycle; -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} cycloalkenyl; heterocyclic And
R ₃ and R ₄ are
(I) hydrogen,
(Ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(Iii) heterocycloalkyl or substituted heterocycloalkyl,
(Iv) each O, _-C 1 _{-C 8} alkyl containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenyl, or _-C 2 -C ₈ Alkynyl; substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C _2- , each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N C _{8 alkynyl;} independently heterocyclic or substituted heterocyclic; -C 3 _{-C 12} cycloalkyl or substituted _-C 3 _{-C 12 cycloalkyl;} -C 3 _{-C 12} cycloalkenyl or substituted _-C 3 _{-C 12} cycloalkenyl Selected,
Alternatively, R ₃ and R ₄ together with the nitrogen to which they are attached form a heterocycle or substituted heterocycle,
Q ₁ and _{Q 2} is selected from halogen or we independently,
X is absent, or (1) oxygen,
(2) sulfur,
(3) NR ₄ ; (R ₄ is as defined above),
(4) -O-NH-
Selected from the group consisting of
Y is absent, or (i) -C (= O)-, -C (= O) -NH-, -S (O) 2-, -S (O) 2NH-,
(Ii) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 1 -C ₆ alkylene containing pieces of heteroatoms,
(Iii) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 2 -C ₆ alkenylene alkylene containing pieces of heteroatoms,
(Iv) 0, 1, 2 or 3 selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl _-C 2 -C ₆ Arukini alkylene containing pieces of heteroatoms,
_{(V) -C} 3 -C ₁₂ cycloalkyl alkylene, substituted _-C 3 _{-C 12} cycloalkyl alkylene, heterocycloalkylene, is selected from the group consisting of substituted heterocycloalkylene <br/>,
W is aryl, substituted arylene, heteroarylene Ren, substituted heteroarylene alkylene, cycloalkyl alkylene, substituted cycloalkyl alkylene, heterocycloalkylene, is selected from the group consisting of substituted heterocycloalkylene, each of which one or more aryl, Substituted aryl, heteroaryl; optionally fused with substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
Or -X-Y-W together

Where W ₁ is
(I) arylene,
(Ii) substituted arylene,
(Iii) heteroarylene Ren,
(Iv) substituted heteroarylene Ren,
( V ) a divalent heterocyclic ring or a substituted divalent heterocyclic ring,
(Vi) each O, _-C 1 _{-C 8} alkylene containing 0, 1, 2 or 3 heteroatoms selected from S or N, _-C 2 _{-C 8} alkenylene alkylene or -C ₂ - C ₈ Arukini Ren,
(Vii) substituted _-C each is O, containing 0, 1, 2 or 3 heteroatoms selected from S or N 1 -C ₈ alkylene, substituted _-C 2 -C ₈ alkenylene alkylene or substituted - C ₂ -C ₈ Arukini Ren,
(Viii) _-C 3 _{-C 12} cycloalkyl Ren,
(Ix) substituted _-C 3 _{-C 12} cycloalkyl alkylene,
(X) _-C 3 _{-C 12} cycloalkenyl Ren,
(Xi) independently selected from the group consisting of substituted _-C 3 _{-C 12} cycloalkenyl Ren <br/>,
W ₂ is
(I) hydrogen,
(Ii) aryl,
(Iii) substituted aryl,
(Iv) heteroaryl,
(V) substituted heteroaryl,
(Vi) a heterocycle or substituted heterocycle,
(Vii) —C ₁ -C ₈ alkyl, —C ₂ -C ₈ alkenyl or —C ₂ -C ₈ each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N Alkynyl,
(Viii) substituted -C ₁ -C ₈ alkyl, substituted -C ₂ -C ₈ alkenyl or substituted -C ₂ each containing 0, 1, 2 or 3 heteroatoms selected from O, S or N -C ₈ alkynyl,
_{(Ix) -C} 3 -C ₁₂ cycloalkyl,
(X) substituted _-C 3 _{-C 12} cycloalkyl,
_{(Xi) -C} 3 -C ₁₂ cycloalkenyl,
(Xii) substituted _-C 3 _{-C 12} cycloalkenyl
Selected independently from the group consisting of
Or _{W 1} and _{W 2} together with the carbon atom to which they are attached, _-C 3 -C ₈ cycloalkyl alkylene, _-C 3 -C ₈ cycloalkenyl Ren, divalent heterocyclic, substituted _-C 3 -C ₈ cycloalkyl alkylene, cyclic moiety selected from the group consisting of substituted -C ₃ -C ₈ cycloalkenyl alkylene and substituted divalent heterocyclic to form, each of which one or more aryl, substituted aryl, heteroaryl, substituted heteroaryl Optionally fused with an aryl, heterocycle or substituted heterocycle;
However, X is oxygen, and when Y is absent, W is a condition that it will not contain a quinoxaline ring system,
m is 0, 1, 2 or 3;
m ′ is 0, 1, 2 or 3, and s is 1, 2, 3 or 4. ]. Formula II

Or a pharmaceutically acceptable salt thereof , wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , W ₁ , W ₂ , Q ₁ , Q ₂ and G are As defined previously in claim 1). Formula III

Or a pharmaceutically acceptable salt thereof , wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , W ₁ , W ₂ , Q ₁ , Q ₂ and G are As defined previously in claim 1). Formula IV, V or VI

Or a pharmaceutically acceptable salt thereof wherein R ₃₀₁ is H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, —CH ₂ -alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ - diarylamino, - (C = O) - alkylamino, - (C = O) - dialkylamino, - (C = O) - arylamino ,-(C = O) -diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or substituted heterocycloalkyl , _{wherein, R, A, L 201,} M, L 101, Z 101, Q 1, Q 2 Oyo G is as defined previously in claim 1. ]. Formula VII or VIII

Or a pharmaceutically acceptable salt thereof , wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , Q ₁ , Q ₂ and G are as defined previously in claim 1 As defined). Formula IX or X

Or a pharmaceutically acceptable salt thereof , wherein R, A, L ₂₀₁ , M, L ₁₀₁ , Z ₁₀₁ , Q ₁ , Q ₂ and G are as defined previously in claim 1 As defined). 2. A compound according to claim 1 selected from compounds of formula XI, wherein R, ML and G are represented in each example in Table 1.

2. A compound according to claim 1, selected from compounds of formula XII, wherein R, ML and G are represented in each example in Table 2.

2. A compound according to claim 1 selected from compounds of formula XIII, wherein R, M-L and G are represented in each example in Table 3.

2. A compound according to claim 1 selected from compounds of formula XIV, wherein R, ML and G are represented in each example in Table 4.